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  • Models, Molecular  (484)
  • Phylogeny  (294)
  • Nature Publishing Group (NPG)  (666)
  • Springer  (100)
  • American Institute of Physics (AIP)
  • 2010-2014  (666)
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  • 1
    Publication Date: 2014-10-09
    Description: The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pancera, Marie -- Zhou, Tongqing -- Druz, Aliaksandr -- Georgiev, Ivelin S -- Soto, Cinque -- Gorman, Jason -- Huang, Jinghe -- Acharya, Priyamvada -- Chuang, Gwo-Yu -- Ofek, Gilad -- Stewart-Jones, Guillaume B E -- Stuckey, Jonathan -- Bailer, Robert T -- Joyce, M Gordon -- Louder, Mark K -- Tumba, Nancy -- Yang, Yongping -- Zhang, Baoshan -- Cohen, Myron S -- Haynes, Barton F -- Mascola, John R -- Morris, Lynn -- Munro, James B -- Blanchard, Scott C -- Mothes, Walther -- Connors, Mark -- Kwong, Peter D -- AI0678501/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P01 GM056550/GM/NIGMS NIH HHS/ -- P01-GM56550/GM/NIGMS NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- R01 GM098859/GM/NIGMS NIH HHS/ -- R01-GM098859/GM/NIGMS NIH HHS/ -- R21 AI100696/AI/NIAID NIH HHS/ -- R21-AI100696/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- ZIA AI005023-13/Intramural NIH HHS/ -- ZIA AI005024-13/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa. ; Departments of Medicine, Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina 27710, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa [2] University of the Witwatersrand, Braamfontein, Johannesburg 2000, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban 4041, South Africa. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296255" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Sequence ; Antibodies, Neutralizing/immunology ; Cohort Studies ; Crystallography, X-Ray ; Genetic Variation ; Glycosylation ; HIV Antibodies/immunology ; HIV Envelope Protein gp120/*chemistry/genetics/*immunology ; HIV Envelope Protein gp41/*chemistry/genetics/*immunology ; HIV Infections/immunology ; Humans ; Immune Evasion ; Membrane Fusion ; Models, Molecular ; Molecular Sequence Data ; Polysaccharides/chemistry/immunology ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/genetics/immunology ; Structural Homology, Protein ; Virus Internalization
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  • 2
    Publication Date: 2014-10-09
    Description: The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals, suggesting that several somatic mutations may be required for their development. To address this, here we characterize 197 anti-stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pappas, Leontios -- Foglierini, Mathilde -- Piccoli, Luca -- Kallewaard, Nicole L -- Turrini, Filippo -- Silacci, Chiara -- Fernandez-Rodriguez, Blanca -- Agatic, Gloria -- Giacchetto-Sasselli, Isabella -- Pellicciotta, Gabriele -- Sallusto, Federica -- Zhu, Qing -- Vicenzi, Elisa -- Corti, Davide -- Lanzavecchia, Antonio -- U19 AI-057266/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):418-22. doi: 10.1038/nature13764. Epub 2014 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. ; Department of Infectious Diseases and Vaccines MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, USA. ; Viral Pathogens and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland. ; Unit of Preventive Medicine, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland [3]. ; 1] Insitute for Research in Biomedicine, Universita della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland [2] Insitute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296253" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Antibodies, Neutralizing/*genetics ; Cells, Cultured ; Complementarity Determining Regions/chemistry/*genetics ; Female ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Humans ; Immunoglobulin Heavy Chains/genetics ; Influenza, Human/*immunology/virology ; Male ; Middle Aged ; Models, Molecular ; Mutation/*genetics ; Orthomyxoviridae/*immunology/metabolism ; Polymorphism, Genetic ; Protein Binding/genetics ; Protein Structure, Tertiary ; Young Adult
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  • 3
    Publication Date: 2014-09-16
    Description: A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Hugo J -- Bronner, Marianne E -- Krumlauf, Robb -- R01 DE017911/DE/NIDCR NIH HHS/ -- R01 NS086907/NS/NINDS NIH HHS/ -- R01DE017911/DE/NIDCR NIH HHS/ -- R01NS086907/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):490-3. doi: 10.1038/nature13723. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; 1] Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA [2] Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City, Kansas 66160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Body Patterning/genetics ; Conserved Sequence/*genetics ; Enhancer Elements, Genetic/genetics ; *Evolution, Molecular ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks/*genetics ; Genes, Homeobox/*genetics ; Lampreys/embryology/genetics ; Molecular Sequence Data ; Phylogeny ; Rhombencephalon/*embryology/*metabolism ; Vertebrates/*embryology/genetics ; Zebrafish/embryology/genetics
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  • 4
    Publication Date: 2014-02-28
    Description: The NRT1/PTR family of proton-coupled transporters are responsible for nitrogen assimilation in eukaryotes and bacteria through the uptake of peptides. However, in most plant species members of this family have evolved to transport nitrate as well as additional secondary metabolites and hormones. In response to falling nitrate levels, NRT1.1 is phosphorylated on an intracellular threonine that switches the transporter from a low-affinity to high-affinity state. Here we present both the apo and nitrate-bound crystal structures of Arabidopsis thaliana NRT1.1, which together with in vitro binding and transport data identify a key role for His 356 in nitrate binding. Our data support a model whereby phosphorylation increases structural flexibility and in turn the rate of transport. Comparison with peptide transporters further reveals how the NRT1/PTR family has evolved to recognize diverse nitrogenous ligands, while maintaining elements of a conserved coupling mechanism within this superfamily of nutrient transporters.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982047/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982047/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Joanne L -- Newstead, Simon -- G0900399/Medical Research Council/United Kingdom -- England -- Nature. 2014 Mar 6;507(7490):68-72. doi: 10.1038/nature13116. Epub 2014 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; 1] Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK [2] Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot OX11 0FA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572366" target="_blank"〉PubMed〈/a〉
    Keywords: Anion Transport Proteins/*chemistry/*metabolism ; Arabidopsis/*chemistry/metabolism ; Crystallography, X-Ray ; Histidine/chemistry/metabolism ; Ion Transport ; Models, Molecular ; Nitrates/chemistry/*metabolism ; Phosphorylation ; Phosphothreonine/metabolism ; Plant Proteins/*chemistry/*metabolism ; Protein Conformation ; Protons ; Structure-Activity Relationship ; Substrate Specificity
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  • 5
    Publication Date: 2014-12-04
    Description: Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport, and is implicated in viral infections and neurodegenerative diseases. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate. The structure reveals a closure of the motor's ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1-AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Helgo -- Zalyte, Ruta -- Urnavicius, Linas -- Carter, Andrew P -- 100387/Wellcome Trust/United Kingdom -- MC_UP_A025_1011/Medical Research Council/United Kingdom -- WT100387/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Feb 19;518(7539):435-8. doi: 10.1038/nature14023. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Division of Structural Studies, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470043" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/analogs & derivatives/metabolism ; Binding Sites ; Crystallography, X-Ray ; *Cytoplasm ; Cytoplasmic Dyneins/*chemistry/*metabolism ; Humans ; Hydrolysis ; Models, Molecular ; Movement ; Protein Conformation
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  • 6
    Publication Date: 2014-11-05
    Description: ATP-binding cassette (ABC) transporters translocate substrates across cell membranes, using energy harnessed from ATP binding and hydrolysis at their nucleotide-binding domains. ABC exporters are present both in prokaryotes and eukaryotes, with examples implicated in multidrug resistance of pathogens and cancer cells, as well as in many human diseases. TmrAB is a heterodimeric ABC exporter from the thermophilic Gram-negative eubacterium Thermus thermophilus; it is homologous to various multidrug transporters and contains one degenerate site with a non-catalytic residue next to the Walker B motif. Here we report a subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy. The reconstructions clearly resolve characteristic features of ABC transporters, including helices in the transmembrane domain and nucleotide-binding domains. A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Furthermore, comparison between our structure and the crystal structures of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372080/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372080/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, JungMin -- Wu, Shenping -- Tomasiak, Thomas M -- Mergel, Claudia -- Winter, Michael B -- Stiller, Sebastian B -- Robles-Colmanares, Yaneth -- Stroud, Robert M -- Tampe, Robert -- Craik, Charles S -- Cheng, Yifan -- 1P41CA196276-01/CA/NCI NIH HHS/ -- P41 CA196276/CA/NCI NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50GM073210/GM/NIGMS NIH HHS/ -- P50GM082250/GM/NIGMS NIH HHS/ -- R01 GM024485/GM/NIGMS NIH HHS/ -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- R37GM024485/GM/NIGMS NIH HHS/ -- S10 RR026814/RR/NCRR NIH HHS/ -- S10RR026814/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):396-400. doi: 10.1038/nature13872. Epub 2014 Nov 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, California 94158, USA. ; Department of Biochemistry and Biophysics, University of California San Francisco, 600 16th Street, San Francisco, California 94158, USA. ; Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany. ; 1] Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, California 94158, USA [2] Department of Biochemistry and Biophysics, University of California San Francisco, 600 16th Street, San Francisco, California 94158, USA. ; 1] Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany [2] Cluster of Excellence - Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363761" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/immunology/*ultrastructure ; Antigens/chemistry/immunology ; Binding Sites ; *Cryoelectron Microscopy ; Crystallography, X-Ray ; Models, Molecular ; Nucleotides/metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Rotation ; Thermus thermophilus/*chemistry
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  • 7
    Publication Date: 2014-10-21
    Description: Organohalide chemistry underpins many industrial and agricultural processes, and a large proportion of environmental pollutants are organohalides. Nevertheless, organohalide chemistry is not exclusively of anthropogenic origin, with natural abiotic and biological processes contributing to the global halide cycle. Reductive dehalogenases are responsible for biological dehalogenation in organohalide respiring bacteria, with substrates including polychlorinated biphenyls or dioxins. Reductive dehalogenases form a distinct subfamily of cobalamin (B12)-dependent enzymes that are usually membrane associated and oxygen sensitive, hindering detailed studies. Here we report the characterization of a soluble, oxygen-tolerant reductive dehalogenase and, by combining structure determination with EPR (electron paramagnetic resonance) spectroscopy and simulation, show that a direct interaction between the cobalamin cobalt and the substrate halogen underpins catalysis. In contrast to the carbon-cobalt bond chemistry catalysed by the other cobalamin-dependent subfamilies, we propose that reductive dehalogenases achieve reduction of the organohalide substrate via halogen-cobalt bond formation. This presents a new model in both organohalide and cobalamin (bio)chemistry that will guide future exploitation of these enzymes in bioremediation or biocatalysis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payne, Karl A P -- Quezada, Carolina P -- Fisher, Karl -- Dunstan, Mark S -- Collins, Fraser A -- Sjuts, Hanno -- Levy, Colin -- Hay, Sam -- Rigby, Stephen E J -- Leys, David -- BB/H021523/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jan 22;517(7535):513-6. doi: 10.1038/nature13901. Epub 2014 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Manchester Institute for Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25327251" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Cobalt/chemistry/metabolism ; Crystallography, X-Ray ; Electron Spin Resonance Spectroscopy ; *Halogenation ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases/*chemistry/*metabolism ; Oxygen/metabolism ; Phenols/chemistry/metabolism ; Phyllobacteriaceae/*enzymology ; Protein Conformation ; Solubility ; Vitamin B 12/chemistry/*metabolism
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  • 8
    Publication Date: 2014-11-05
    Description: Human immunodeficiency virus type 1 (HIV-1) assembly proceeds in two stages. First, the 55 kilodalton viral Gag polyprotein assembles into a hexameric protein lattice at the plasma membrane of the infected cell, inducing budding and release of an immature particle. Second, Gag is cleaved by the viral protease, leading to internal rearrangement of the virus into the mature, infectious form. Immature and mature HIV-1 particles are heterogeneous in size and morphology, preventing high-resolution analysis of their protein arrangement in situ by conventional structural biology methods. Here we apply cryo-electron tomography and sub-tomogram averaging methods to resolve the structure of the capsid lattice within intact immature HIV-1 particles at subnanometre resolution, allowing unambiguous positioning of all alpha-helices. The resulting model reveals tertiary and quaternary structural interactions that mediate HIV-1 assembly. Strikingly, these interactions differ from those predicted by the current model based on in vitro-assembled arrays of Gag-derived proteins from Mason-Pfizer monkey virus. To validate this difference, we solve the structure of the capsid lattice within intact immature Mason-Pfizer monkey virus particles. Comparison with the immature HIV-1 structure reveals that retroviral capsid proteins, while having conserved tertiary structures, adopt different quaternary arrangements during virus assembly. The approach demonstrated here should be applicable to determine structures of other proteins at subnanometre resolution within heterogeneous environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schur, Florian K M -- Hagen, Wim J H -- Rumlova, Michaela -- Ruml, Tomas -- Muller, Barbara -- Krausslich, Hans-Georg -- Briggs, John A G -- England -- Nature. 2015 Jan 22;517(7535):505-8. doi: 10.1038/nature13838. Epub 2014 Nov 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany [2] Molecular Medicine Partnership Unit, European Molecular Biology Laboratory/Universitatsklinikum Heidelberg, Heidelberg, Germany. ; Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. ; 1] Institute of Organic Chemistry and Biochemistry (IOCB), Academy of Sciences of the Czech Republic, v.v.i., IOCB &Gilead Research Center, Flemingovo nam. 2, 166 10 Prague, Czech Republic [2] Department of Biotechnology, Institute of Chemical Technology, Prague, Technicka 5, 166 28, Prague, Czech Republic. ; Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague, Technicka 5, 166 28, Prague, Czech Republic. ; 1] Molecular Medicine Partnership Unit, European Molecular Biology Laboratory/Universitatsklinikum Heidelberg, Heidelberg, Germany [2] Department of Infectious Diseases, Virology, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363765" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid/chemistry/*ultrastructure ; Capsid Proteins/chemistry/ultrastructure ; *Cryoelectron Microscopy ; *Electron Microscope Tomography ; HEK293 Cells ; HIV-1/*chemistry/*ultrastructure ; Humans ; Mason-Pfizer monkey virus/chemistry/ultrastructure ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Virion/*chemistry/*ultrastructure ; Virus Assembly
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  • 9
    Publication Date: 2014-11-11
    Description: DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Xue -- Wang, Ling -- Li, Jie -- Ding, Zhanyu -- Xiao, Jianxiong -- Yin, Xiaotong -- He, Shuang -- Shi, Pan -- Dong, Liping -- Li, Guohong -- Tian, Changlin -- Wang, Jiawei -- Cong, Yao -- Xu, Yanhui -- England -- Nature. 2015 Jan 29;517(7536):640-4. doi: 10.1038/nature13899. Epub 2014 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [2] State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China. ; Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; 1] High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China [2] National Laboratory for Physical Science at the Microscale, University of Science and Technology of China, Hefei 230026, China [3] School of Life Sciences, University of Science and Technology of China, Hefei 230026, China. ; 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China [2] University of Chinese Academy of Science, Beijing 100049, China. ; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China. ; State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA (Cytosine-5-)-Methyltransferase/*antagonists & ; inhibitors/*chemistry/*metabolism ; DNA Methylation ; Enzyme Activation ; Histones/*chemistry/*metabolism ; Humans ; Mice ; Models, Molecular ; Protein Structure, Tertiary ; Xenopus laevis
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  • 10
    Publication Date: 2014-12-04
    Description: Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections, and multiple variations of myopathies. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin. Although crystal structures for monomeric actin (G-actin) are available, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 A in complex with tropomyosin at a resolution of 6.5 A, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg(2+) and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin-tropomyosin with its position in our previously determined F-actin-tropomyosin-myosin structure reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477711/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477711/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von der Ecken, Julian -- Muller, Mirco -- Lehman, William -- Manstein, Dietmar J -- Penczek, Pawel A -- Raunser, Stefan -- R01 60635/PHS HHS/ -- R01 GM060635/GM/NIGMS NIH HHS/ -- R37HL036153/HL/NHLBI NIH HHS/ -- U54 094598/PHS HHS/ -- U54 GM094598/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):114-7. doi: 10.1038/nature14033. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany. ; Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas, Houston Medical School, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470062" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*chemistry/genetics/*metabolism ; Adenosine Diphosphate/metabolism ; Animals ; Cryoelectron Microscopy ; Magnesium/metabolism ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Conformation ; Rabbits ; Static Electricity ; Tropomyosin/*chemistry/genetics/*metabolism
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  • 11
    Publication Date: 2014-11-05
    Description: Lantibiotics are a class of peptide antibiotics that contain one or more thioether bonds. The lantibiotic nisin is an antimicrobial peptide that is widely used as a food preservative to combat food-borne pathogens. Nisin contains dehydroalanine and dehydrobutyrine residues that are formed by the dehydration of Ser/Thr by the lantibiotic dehydratase NisB (ref. 2). Recent biochemical studies revealed that NisB glutamylates Ser/Thr side chains as part of the dehydration process. However, the molecular mechanism by which NisB uses glutamate to catalyse dehydration remains unresolved. Here we show that this process involves glutamyl-tRNA(Glu) to activate Ser/Thr residues. In addition, the 2.9-A crystal structure of NisB in complex with its substrate peptide NisA reveals the presence of two separate domains that catalyse the Ser/Thr glutamylation and glutamate elimination steps. The co-crystal structure also provides insights into substrate recognition by lantibiotic dehydratases. Our findings demonstrate an unexpected role for aminoacyl-tRNA in the formation of dehydroamino acids in lantibiotics, and serve as a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430201/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430201/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ortega, Manuel A -- Hao, Yue -- Zhang, Qi -- Walker, Mark C -- van der Donk, Wilfred A -- Nair, Satish K -- 5T32-GM070421/GM/NIGMS NIH HHS/ -- F32 GM112284/GM/NIGMS NIH HHS/ -- R01 GM 058822/GM/NIGMS NIH HHS/ -- R01 GM058822/GM/NIGMS NIH HHS/ -- R01 GM079038/GM/NIGMS NIH HHS/ -- S10 RR027109 A/RR/NCRR NIH HHS/ -- T32 GM070421/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jan 22;517(7535):509-12. doi: 10.1038/nature13888. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA. ; Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA. ; 1] Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA [2] Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA. ; 1] Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363770" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/classification/*metabolism ; Bacteriocins/biosynthesis/*metabolism ; Crystallography, X-Ray ; Escherichia coli/genetics ; Glutamic Acid/metabolism ; Hydro-Lyases/*chemistry/classification/*metabolism ; Lactococcus lactis/*enzymology/genetics ; Membrane Proteins/*chemistry/classification/*metabolism ; Models, Molecular ; Nisin/biosynthesis/metabolism ; Phylogeny ; Protein Structure, Tertiary ; RNA, Transfer, Glu/genetics/*metabolism ; Serine/metabolism ; Threonine/metabolism
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  • 12
    Publication Date: 2014-12-04
    Description: Muscle contraction is initiated by the release of calcium (Ca(2+)) from the sarcoplasmic reticulum into the cytoplasm of myocytes through ryanodine receptors (RyRs). RyRs are homotetrameric channels with a molecular mass of more than 2.2 megadaltons that are regulated by several factors, including ions, small molecules and proteins. Numerous mutations in RyRs have been associated with human diseases. The molecular mechanism underlying the complex regulation of RyRs is poorly understood. Using electron cryomicroscopy, here we determine the architecture of rabbit RyR1 at a resolution of 6.1 A. We show that the cytoplasmic moiety of RyR1 contains two large alpha-solenoid domains and several smaller domains, with folds suggestive of participation in protein-protein interactions. The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. We identify the calcium-binding EF-hand domain and show that it functions as a conformational switch allosterically gating the channel.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Efremov, Rouslan G -- Leitner, Alexander -- Aebersold, Ruedi -- Raunser, Stefan -- England -- Nature. 2015 Jan 1;517(7532):39-43. doi: 10.1038/nature13916. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany [2] Structural Biology Research Center, Vlaams Instituut voor Biotechnologie (VIB), 1050 Brussels, Belgium [3] Structural Biology Brussels, Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium. ; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. ; 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, 8057 Zurich, Switzerland. ; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470059" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Animals ; Calcium/deficiency/metabolism/pharmacology ; Cryoelectron Microscopy ; Cytoplasm/metabolism ; Hydrogen-Ion Concentration ; Inositol 1,4,5-Trisphosphate Receptors/chemistry ; Ion Channel Gating/drug effects ; Models, Molecular ; Protein Binding ; Protein Structure, Tertiary/drug effects ; Rabbits ; Ryanodine Receptor Calcium Release Channel/chemistry/*metabolism/*ultrastructure ; Tacrolimus Binding Protein 1A/chemistry/metabolism/ultrastructure
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  • 13
    Publication Date: 2014-05-30
    Description: The self-assembly of proteins into highly ordered nanoscale architectures is a hallmark of biological systems. The sophisticated functions of these molecular machines have inspired the development of methods to engineer self-assembling protein nanostructures; however, the design of multi-component protein nanomaterials with high accuracy remains an outstanding challenge. Here we report a computational method for designing protein nanomaterials in which multiple copies of two distinct subunits co-assemble into a specific architecture. We use the method to design five 24-subunit cage-like protein nanomaterials in two distinct symmetric architectures and experimentally demonstrate that their structures are in close agreement with the computational design models. The accuracy of the method and the number and variety of two-component materials that it makes accessible suggest a route to the construction of functional protein nanomaterials tailored to specific applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137318/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137318/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉King, Neil P -- Bale, Jacob B -- Sheffler, William -- McNamara, Dan E -- Gonen, Shane -- Gonen, Tamir -- Yeates, Todd O -- Baker, David -- T32 GM067555/GM/NIGMS NIH HHS/ -- T32GM067555/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 5;510(7503):103-8. doi: 10.1038/nature13404. Epub 2014 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA [3]. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98195, USA [3]. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2]. ; UCLA Department of Chemistry and Biochemistry, Los Angeles, California 90095, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, USA. ; Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, USA. ; 1] UCLA Department of Chemistry and Biochemistry, Los Angeles, California 90095, USA [2] UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, California 90095, USA [3] UCLA Molecular Biology Institute, Los Angeles, California 90095, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA [3] Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870237" target="_blank"〉PubMed〈/a〉
    Keywords: Computer Simulation ; Crystallography, X-Ray ; Drug Design ; Models, Molecular ; Nanostructures/*chemistry/ultrastructure ; Protein Subunits/chemistry ; Proteins/*chemistry/ultrastructure
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  • 14
    Publication Date: 2014-08-21
    Description: Modern strains of Mycobacterium tuberculosis from the Americas are closely related to those from Europe, supporting the assumption that human tuberculosis was introduced post-contact. This notion, however, is incompatible with archaeological evidence of pre-contact tuberculosis in the New World. Comparative genomics of modern isolates suggests that M. tuberculosis attained its worldwide distribution following human dispersals out of Africa during the Pleistocene epoch, although this has yet to be confirmed with ancient calibration points. Here we present three 1,000-year-old mycobacterial genomes from Peruvian human skeletons, revealing that a member of the M. tuberculosis complex caused human disease before contact. The ancient strains are distinct from known human-adapted forms and are most closely related to those adapted to seals and sea lions. Two independent dating approaches suggest a most recent common ancestor for the M. tuberculosis complex less than 6,000 years ago, which supports a Holocene dispersal of the disease. Our results implicate sea mammals as having played a role in transmitting the disease to humans across the ocean.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550673/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550673/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bos, Kirsten I -- Harkins, Kelly M -- Herbig, Alexander -- Coscolla, Mireia -- Weber, Nico -- Comas, Inaki -- Forrest, Stephen A -- Bryant, Josephine M -- Harris, Simon R -- Schuenemann, Verena J -- Campbell, Tessa J -- Majander, Kerttu -- Wilbur, Alicia K -- Guichon, Ricardo A -- Wolfe Steadman, Dawnie L -- Cook, Della Collins -- Niemann, Stefan -- Behr, Marcel A -- Zumarraga, Martin -- Bastida, Ricardo -- Huson, Daniel -- Nieselt, Kay -- Young, Douglas -- Parkhill, Julian -- Buikstra, Jane E -- Gagneux, Sebastien -- Stone, Anne C -- Krause, Johannes -- 098051/Wellcome Trust/United Kingdom -- AI090928/AI/NIAID NIH HHS/ -- MC_U117581288/Medical Research Council/United Kingdom -- R01 AI090928/AI/NIAID NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Oct 23;514(7523):494-7. doi: 10.1038/nature13591. Epub 2014 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2]. ; 1] School of Human Evolution and Social Change, Arizona State University, PO Box 872402, Tempe, Arizona 85287-2402, USA [2]. ; 1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2] Center for Bioinformatics, University of Tubingen, Sand 14, 72076 Tubingen, Germany [3]. ; 1] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland [2] University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland [3]. ; Center for Bioinformatics, University of Tubingen, Sand 14, 72076 Tubingen, Germany. ; 1] Genomics and Health Unit, FISABIO-Public Health, Avenida Cataluna 21, 46020 Valencia, Spain [2] CIBER (Centros de Investigacion Biomedica en Red) in Epidemiology and Public Health, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellon 11, Planta 0, 28029 Madrid, Spain. ; Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany. ; Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Archaeology, University of Cape Town, Private Bag X1, Rondebosch, 7701, South Africa. ; School of Human Evolution and Social Change, Arizona State University, PO Box 872402, Tempe, Arizona 85287-2402, USA. ; CONICET, Laboratorio de Ecologia Evolutiva Humana (FACSO, UNCPBA), Departamento de Biologia (FCEyN, UNMDP), Calle 508 No. 881 (7631), Quequen, Argentina. ; Department of Anthropology, University of Tennessee, 250 South Stadium Hall, Knoxville, Tennessee 37996, USA. ; Department of Anthropology, Indiana University, 701 East Kirkwood Avenue, Bloomington, Indiana 47405-7100, USA. ; 1] Molecular Mycobacteriology, Forschungszentrum Borstel, Parkallee 1, 23845 Borstel, Germany [2] German Center for Infection Research, Forschungszentrum Borstel, Parkallee 1, 23845 Borstel, Germany. ; McGill International TB Centre, McGill University, 1650 Cedar Avenue, Montreal H3G 1A4, Canada. ; Biotechnology Institute, CICVyA-INTA Castelar, Dr. Nicolas Repetto y De Los Reseros S/N, (B1686IGC) Hurlingham, Buenos Aires, Argentina. ; Instituto de Investigaciones Marinas y Costeras (CONICET-UNMdP), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, San Luis 1722, Mar del Plata 7600, Argentina. ; 1] Department of Medicine, Imperial College, London W2 1PG, UK [2] Division of Mycobacterial Research, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. ; 1] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland [2] University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland. ; 1] Department of Archaeological Sciences, University of Tubingen, Ruemelinstrasse 23, 72070 Tubingen, Germany [2] Senckenberg Centre for Human Evolution and Palaeoenvironment, University of Tubingen, Tubingen 72070, Germany [3] Max Planck Institute for Science and History, Khalaische Strasse 10, 07745 Jena, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25141181" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone and Bones/microbiology ; Europe/ethnology ; Genome, Bacterial/*genetics ; Genomics ; History, Ancient ; Human Migration/history ; Humans ; Mycobacterium tuberculosis/*genetics ; Peru ; Phylogeny ; Pinnipedia/*microbiology ; Tuberculosis/*history/*microbiology/transmission ; Zoonoses/*history/*microbiology/transmission
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  • 15
    Publication Date: 2014-03-29
    Description: In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequence chi (Chi) and is catalysed by either an AddAB- or RecBCD-type helicase-nuclease (reviewed in refs 3, 4). These enzyme complexes unwind and digest the DNA duplex from the broken end until they encounter a chi sequence, whereupon they produce a 3' single-stranded DNA tail onto which they initiate loading of the RecA protein. Consequently, regulation of the AddAB/RecBCD complex by chi is a key control point in DNA repair and other processes involving genetic recombination. Here we report crystal structures of Bacillus subtilis AddAB in complex with different chi-containing DNA substrates either with or without a non-hydrolysable ATP analogue. Comparison of these structures suggests a mechanism for DNA translocation and unwinding, suggests how the enzyme binds specifically to chi sequences, and explains how chi recognition leads to the arrest of AddAB (and RecBCD) translocation that is observed in single-molecule experiments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991583/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krajewski, Wojciech W -- Fu, Xin -- Wilkinson, Martin -- Cronin, Nora B -- Dillingham, Mark S -- Wigley, Dale B -- 100401/Wellcome Trust/United Kingdom -- 12799/Cancer Research UK/United Kingdom -- A12799/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 17;508(7496):416-9. doi: 10.1038/nature13037. Epub 2014 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK [2] CRT Discovery Laboratories, Department of Biological Sciences, Birkbeck, University of London, London WC1E 7HX, UK. ; Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. ; School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670664" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/analogs & derivatives/metabolism ; Bacillus subtilis/*enzymology ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/genetics/metabolism ; DNA Helicases/*chemistry/metabolism ; Exodeoxyribonucleases/*chemistry/*metabolism ; Models, Molecular ; Molecular Conformation ; Recombination, Genetic/*genetics ; Structure-Activity Relationship
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  • 16
    Publication Date: 2014-03-05
    Description: Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395007/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doria-Rose, Nicole A -- Schramm, Chaim A -- Gorman, Jason -- Moore, Penny L -- Bhiman, Jinal N -- DeKosky, Brandon J -- Ernandes, Michael J -- Georgiev, Ivelin S -- Kim, Helen J -- Pancera, Marie -- Staupe, Ryan P -- Altae-Tran, Han R -- Bailer, Robert T -- Crooks, Ema T -- Cupo, Albert -- Druz, Aliaksandr -- Garrett, Nigel J -- Hoi, Kam H -- Kong, Rui -- Louder, Mark K -- Longo, Nancy S -- McKee, Krisha -- Nonyane, Molati -- O'Dell, Sijy -- Roark, Ryan S -- Rudicell, Rebecca S -- Schmidt, Stephen D -- Sheward, Daniel J -- Soto, Cinque -- Wibmer, Constantinos Kurt -- Yang, Yongping -- Zhang, Zhenhai -- NISC Comparative Sequencing Program -- Mullikin, James C -- Binley, James M -- Sanders, Rogier W -- Wilson, Ian A -- Moore, John P -- Ward, Andrew B -- Georgiou, George -- Williamson, Carolyn -- Abdool Karim, Salim S -- Morris, Lynn -- Kwong, Peter D -- Shapiro, Lawrence -- Mascola, John R -- P01 AI082362/AI/NIAID NIH HHS/ -- R01 AI100790/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 May 1;509(7498):55-62. doi: 10.1038/nature13036. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2]. ; 1] Department of Biochemistry, Columbia University, New York, New York 10032, USA [2]. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [4]. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa. ; Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA. ; Torrey Pines Institute, San Diego, California 92037, USA. ; Weill Medical College of Cornell University, New York, New York 10065, USA. ; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa. ; Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa. ; Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa. ; Department of Biochemistry, Columbia University, New York, New York 10032, USA. ; 1] NISC Comparative Sequencing program, National Institutes of Health, Bethesda, Maryland 20892, USA [2] NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Medical Microbiology, Academic Medical Center, Amsterdam 1105 AZ, Netherlands. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA [2] Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA [3] Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA. ; 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa. ; 1] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa [2] Department of Epidemiology, Columbia University, New York, New York 10032, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa [2] Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa. ; 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Department of Biochemistry, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590074" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/genetics/*immunology/isolation & purification ; Antibody Affinity/genetics/immunology ; Antigens, CD4/immunology/metabolism ; B-Lymphocytes/cytology/immunology/metabolism ; Binding Sites/immunology ; Cell Lineage ; Complementarity Determining Regions/chemistry/genetics/immunology ; Epitope Mapping ; Epitopes, B-Lymphocyte/chemistry/immunology ; Evolution, Molecular ; HIV Antibodies/chemistry/genetics/*immunology/isolation & purification ; HIV Envelope Protein gp160/*chemistry/*immunology ; HIV Infections/immunology ; HIV-1/chemistry/immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Neutralization Tests ; Protein Structure, Tertiary ; Somatic Hypermutation, Immunoglobulin/genetics
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  • 17
    Publication Date: 2014-06-12
    Description: Knowledge of the early evolution of fish largely depends on soft-bodied material from the Lower (Series 2) Cambrian period of South China. Owing to the rarity of some of these forms and a general lack of comparative material from other deposits, interpretations of various features remain controversial, as do their wider relationships amongst post-Cambrian early un-skeletonized jawless vertebrates. Here we redescribe Metaspriggina on the basis of new material from the Burgess Shale and exceptionally preserved material collected near Marble Canyon, British Columbia, and three other Cambrian Burgess Shale-type deposits from Laurentia. This primitive fish displays unambiguous vertebrate features: a notochord, a pair of prominent camera-type eyes, paired nasal sacs, possible cranium and arcualia, W-shaped myomeres, and a post-anal tail. A striking feature is the branchial area with an array of bipartite bars. Apart from the anterior-most bar, which appears to be slightly thicker, each is associated with externally located gills, possibly housed in pouches. Phylogenetic analysis places Metaspriggina as a basal vertebrate, apparently close to the Chengjiang taxa Haikouichthys and Myllokunmingia, demonstrating also that this primitive group of fish was cosmopolitan during Lower-Middle Cambrian times (Series 2-3). However, the arrangement of the branchial region in Metaspriggina has wider implications for reconstructing the morphology of the primitive vertebrate. Each bipartite bar is identified as being respectively equivalent to an epibranchial and ceratobranchial. This configuration suggests that a bipartite arrangement is primitive and reinforces the view that the branchial basket of lampreys is probably derived. Other features of Metaspriggina, including the external position of the gills and possible absence of a gill opposite the more robust anterior-most bar, are characteristic of gnathostomes and so may be primitive within vertebrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morris, Simon Conway -- Caron, Jean-Bernard -- England -- Nature. 2014 Aug 28;512(7515):419-22. doi: 10.1038/nature13414. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EQ, UK. ; 1] Department of Natural History (Palaeobiology), Royal Ontario Museum, 100 Queen's Park, Toronto, Ontario M5S 2C6, Canada [2] University of Toronto, Department of Ecology and Evolutionary Biology, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919146" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; British Columbia ; Fishes/*anatomy & histology ; *Fossils ; Gills/anatomy & histology ; Museums ; Ontario ; Phylogeny
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  • 18
    Publication Date: 2014-07-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stroebel, David -- Paoletti, Pierre -- England -- Nature. 2014 Jul 10;511(7508):162-3. doi: 10.1038/511162a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biology, Ecole Normale Superieure, CNRS UMR8197, INSERM U1024, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25008517" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Humans ; Models, Molecular ; Protein Structure, Tertiary ; Receptors, N-Methyl-D-Aspartate/*chemistry/metabolism/*physiology
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  • 19
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2014-04-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wood, Bernard -- England -- Nature. 2014 Apr 3;508(7494):31-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24707524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asia ; *Biological Evolution ; *Fossils ; History, 20th Century ; Hominidae/anatomy & histology/*classification ; Kenya ; Paleontology/*history ; Phylogeny ; Tanzania
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  • 20
    Publication Date: 2014-08-15
    Description: The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Overexpression of Lin28 is correlated with the onset of numerous cancers, whereas let-7, a tumour suppressor, silences several human oncogenes. Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3' oligo-uridylation activity of TUT4 and TUT7 (refs 10-12). The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by Dis3l2 (refs 13, 14), a homologue of the catalytic subunit of the RNA exosome. The molecular basis of Lin28-mediated recruitment of TUT4 and TUT7 to pre-let-7 and its subsequent degradation by Dis3l2 is largely unknown. To examine the mechanism of Dis3l2 substrate recognition we determined the structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let-7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. We identify three U-specificity zones that explain how Dis3l2 recognizes, binds and processes uridylated pre-let-7 in the final step of the Lin28-let-7 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192074/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192074/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faehnle, Christopher R -- Walleshauser, Jack -- Joshua-Tor, Leemor -- P30 CA045508/CA/NCI NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- T32 GM065094/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):252-6. doi: 10.1038/nature13553. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3]. ; 1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3] Watson School of Biological Science, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA [4]. ; 1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3] Watson School of Biological Science, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA [4] Howard Hughes Medical Institute, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119025" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Exoribonucleases/*chemistry/*metabolism ; Exosome Multienzyme Ribonuclease Complex/chemistry ; Mice ; MicroRNAs/chemistry/genetics/*metabolism ; Models, Molecular ; Oligoribonucleotides/chemistry/metabolism ; RNA-Binding Proteins/chemistry/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry ; Substrate Specificity ; Uracil Nucleotides/chemistry/metabolism
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  • 21
    Publication Date: 2014-02-14
    Description: Extant vertebrates form two clades, the jawless Cyclostomata (lampreys and hagfishes) and the jawed Gnathostomata (all other vertebrates), with contrasting facial architectures. These arise during development from just a few key differences in the growth patterns of the cranial primordia: notably, the nasal sacs and hypophysis originate from a single placode in cyclostomes but from separate placodes in gnathostomes, and infraoptic ectomesenchyme migrates forward either side of the single placode in cyclostomes but between the placodes in gnathostomes. Fossil stem gnathostomes preserve cranial anatomies rich in landmarks that provide proxies for developmental processes and allow the transition from jawless to jawed vertebrates to be broken down into evolutionary steps. Here we use propagation phase contrast synchrotron microtomography to image the cranial anatomy of the primitive placoderm (jawed stem gnathostome) Romundina, and show that it combines jawed vertebrate architecture with cranial and cerebral proportions resembling those of cyclostomes and the galeaspid (jawless stem gnathostome) Shuyu. This combination seems to be primitive for jawed vertebrates, and suggests a decoupling between ectomesenchymal growth trajectory, ectomesenchymal proliferation, and cerebral shape change during the origin of gnathostomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dupret, Vincent -- Sanchez, Sophie -- Goujet, Daniel -- Tafforeau, Paul -- Ahlberg, Per E -- England -- Nature. 2014 Mar 27;507(7493):500-3. doi: 10.1038/nature12980. Epub 2014 Feb 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Uppsala University, Department of Organismal Biology, Subdepartment of Evolution and Development, Norbyvagen 18A, SE-752 36, Uppsala, Sweden. ; 1] Uppsala University, Department of Organismal Biology, Subdepartment of Evolution and Development, Norbyvagen 18A, SE-752 36, Uppsala, Sweden [2] European Synchrotron Radiation Facility, 6 rue Jules Horowitz, 38043 Grenoble Cedex, France. ; Museum national d'Histoire naturelle, UMR 7207 CR2P CNRS/MNHN/UPMC, 8 rue Buffon, CP 38,75231 Paris Cedex 05, France. ; European Synchrotron Radiation Facility, 6 rue Jules Horowitz, 38043 Grenoble Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24522530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Brain/anatomy & histology ; Face/anatomy & histology ; Fishes/*anatomy & histology/classification ; *Fossils ; *Jaw/anatomy & histology ; Lampreys/anatomy & histology ; Neural Crest/anatomy & histology ; Phylogeny
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  • 22
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2014-06-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Kerri -- England -- Nature. 2014 Jun 26;510(7506):458-60. doi: 10.1038/510458a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24965634" target="_blank"〉PubMed〈/a〉
    Keywords: Anthropology ; Cell Division ; *Cooperative Behavior ; Cultural Evolution ; Ecology ; Germany ; Humans ; *Laboratories ; *Love ; Phylogeny ; Research Personnel/*psychology ; Taiwan ; Travel ; Workplace
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  • 23
    Publication Date: 2014-02-28
    Description: Nitrate is a primary nutrient for plant growth, but its levels in soil can fluctuate by several orders of magnitude. Previous studies have identified Arabidopsis NRT1.1 as a dual-affinity nitrate transporter that can take up nitrate over a wide range of concentrations. The mode of action of NRT1.1 is controlled by phosphorylation of a key residue, Thr 101; however, how this post-translational modification switches the transporter between two affinity states remains unclear. Here we report the crystal structure of unphosphorylated NRT1.1, which reveals an unexpected homodimer in the inward-facing conformation. In this low-affinity state, the Thr 101 phosphorylation site is embedded in a pocket immediately adjacent to the dimer interface, linking the phosphorylation status of the transporter to its oligomeric state. Using a cell-based fluorescence resonance energy transfer assay, we show that functional NRT1.1 dimerizes in the cell membrane and that the phosphomimetic mutation of Thr 101 converts the protein into a monophasic high-affinity transporter by structurally decoupling the dimer. Together with analyses of the substrate transport tunnel, our results establish a phosphorylation-controlled dimerization switch that allows NRT1.1 to uptake nitrate with two distinct affinity modes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968801/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Ji -- Bankston, John R -- Payandeh, Jian -- Hinds, Thomas R -- Zagotta, William N -- Zheng, Ning -- NS074545/NS/NINDS NIH HHS/ -- R01EY10329/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 6;507(7490):73-7. doi: 10.1038/nature13074. Epub 2014 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA. ; Department of Physiology and Biophysics, Box 357290, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA [2] Department of Structural Biology, Genentech Inc., South San Francisco, California 94080, USA. ; 1] Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572362" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Anion Transport Proteins/*chemistry/genetics/metabolism ; Arabidopsis/*chemistry/genetics ; Binding Sites ; Biological Transport ; Cell Membrane/chemistry/metabolism ; Crystallography, X-Ray ; Fluorescence Resonance Energy Transfer ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Nitrates/chemistry/metabolism ; Phosphorylation ; Phosphothreonine/chemistry/metabolism ; Plant Proteins/*chemistry/genetics/metabolism ; *Protein Multimerization ; Protein Structure, Quaternary ; Protons ; Structure-Activity Relationship
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  • 24
    Publication Date: 2014-06-27
    Description: Polyketide natural products constitute a broad class of compounds with diverse structural features and biological activities. Their biosynthetic machinery, represented by type I polyketide synthases (PKSs), has an architecture in which successive modules catalyse two-carbon linear extensions and keto-group processing reactions on intermediates covalently tethered to carrier domains. Here we used electron cryo-microscopy to determine sub-nanometre-resolution three-dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture compared to the homologous dimeric mammalian fatty acid synthase. A single reaction chamber provides access to all catalytic sites for the intramodule carrier domain. In contrast, the carrier from the preceding module uses a separate entrance outside the reaction chamber to deliver the upstream polyketide intermediate for subsequent extension and modification. This study reveals for the first time, to our knowledge, the structural basis for both intramodule and intermodule substrate transfer in polyketide synthases, and establishes a new model for molecular dissection of these multifunctional enzyme systems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278352/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278352/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dutta, Somnath -- Whicher, Jonathan R -- Hansen, Douglas A -- Hale, Wendi A -- Chemler, Joseph A -- Congdon, Grady R -- Narayan, Alison R H -- Hakansson, Kristina -- Sherman, David H -- Smith, Janet L -- Skiniotis, Georgios -- 1R21CA138331-01A1/CA/NCI NIH HHS/ -- DK042303/DK/NIDDK NIH HHS/ -- DK090165/DK/NIDDK NIH HHS/ -- GM076477/GM/NIGMS NIH HHS/ -- R01 DK042303/DK/NIDDK NIH HHS/ -- R01 DK090165/DK/NIDDK NIH HHS/ -- R01 GM076477/GM/NIGMS NIH HHS/ -- T32 GM008597/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):512-7. doi: 10.1038/nature13423. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2]. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Chemical Biology Graduate Program, University of Michigan, Ann Arbor, Michigan 48109, USA [3]. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [4] Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24965652" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Cryoelectron Microscopy ; Fatty Acid Synthases/chemistry ; Macrolides/metabolism ; Models, Molecular ; Polyketide Synthases/*chemistry/metabolism/*ultrastructure ; Streptomyces/*enzymology
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  • 25
    Publication Date: 2014-08-22
    Description: Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor, high-resolution X-ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255919/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255919/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Althoff, Thorsten -- Hibbs, Ryan E -- Banerjee, Surajit -- Gouaux, Eric -- F32 NS061404/NS/NINDS NIH HHS/ -- F32NS061404/NS/NINDS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM100400/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Aug 21;512(7514):333-7. doi: 10.1038/nature13669.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095-1751, USA (T.A.); Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9111, USA (R.E.H.). [3]. ; NE-CAT/Cornell University, 9700 South Cass Avenue, Building 436 E001, Argonne, Illinois 60439, USA. ; 1] Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25143115" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Animals ; Apoproteins/*chemistry/metabolism ; Binding Sites ; Binding, Competitive/drug effects ; Caenorhabditis elegans/*chemistry ; Cell Membrane/metabolism ; Chloride Channels/*chemistry/*metabolism ; Crystallography, X-Ray ; Cysteine Loop Ligand-Gated Ion Channel Receptors/*chemistry/*metabolism ; Drug Partial Agonism ; Glutamic Acid/metabolism ; Ion Channel Gating ; Ivermectin/chemistry/metabolism/pharmacology ; Ligands ; Models, Molecular ; Movement/drug effects ; Phosphatidylcholines/chemistry/metabolism/pharmacology ; Protein Binding ; Protein Multimerization/drug effects ; Protein Structure, Tertiary/drug effects ; Structure-Activity Relationship
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  • 26
    Publication Date: 2014-04-18
    Description: Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224315/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224315/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Motlagh, Hesam N -- Wrabl, James O -- Li, Jing -- Hilser, Vincent J -- GM63747/GM/NIGMS NIH HHS/ -- R01 GM063747/GM/NIGMS NIH HHS/ -- T32 GM008403/GM/NIGMS NIH HHS/ -- T32-GM008403/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Apr 17;508(7496):331-9. doi: 10.1038/nature13001.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology and T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24740064" target="_blank"〉PubMed〈/a〉
    Keywords: *Allosteric Regulation ; Allosteric Site ; Hemoglobins/chemistry/metabolism ; Ligands ; Models, Molecular ; Protein Unfolding ; Proteins/*chemistry/*metabolism ; Thermodynamics
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  • 27
    Publication Date: 2014-01-10
    Description: Throughout the animal kingdom, adaptive colouration serves critical functions ranging from inconspicuous camouflage to ostentatious sexual display, and can provide important information about the environment and biology of a particular organism. The most ubiquitous and abundant pigment, melanin, also has a diverse range of non-visual roles, including thermoregulation in ectotherms. However, little is known about the functional evolution of this important biochrome through deep time, owing to our limited ability to unambiguously identify traces of it in the fossil record. Here we present direct chemical evidence of pigmentation in fossilized skin, from three distantly related marine reptiles: a leatherback turtle, a mosasaur and an ichthyosaur. We demonstrate that dark traces of soft tissue in these fossils are dominated by molecularly preserved eumelanin, in intimate association with fossilized melanosomes. In addition, we suggest that contrary to the countershading of many pelagic animals, at least some ichthyosaurs were uniformly dark-coloured in life. Our analyses expand current knowledge of pigmentation in fossil integument beyond that of feathers, allowing for the reconstruction of colour over much greater ranges of extinct taxa and anatomy. In turn, our results provide evidence of convergent melanism in three disparate lineages of secondarily aquatic tetrapods. Based on extant marine analogues, we propose that the benefits of thermoregulation and/or crypsis are likely to have contributed to this melanisation, with the former having implications for the ability of each group to exploit cold environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindgren, Johan -- Sjovall, Peter -- Carney, Ryan M -- Uvdal, Per -- Gren, Johan A -- Dyke, Gareth -- Schultz, Bo Pagh -- Shawkey, Matthew D -- Barnes, Kenneth R -- Polcyn, Michael J -- England -- Nature. 2014 Feb 27;506(7489):484-8. doi: 10.1038/nature12899. Epub 2014 Jan 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geology, Lund University, SE-223 62 Lund, Sweden. ; SP Technical Research Institute of Sweden, Chemistry, Materials and Surfaces, SE-501 15 Boras, Sweden. ; Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island 02906, USA. ; 1] MAX-IV laboratory, Lund University, SE-221 00 Lund, Sweden [2] Chemical Physics, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden. ; 1] Ocean and Earth Sciences, University of Southampton, Southampton SO14 3ZH, UK [2] Institute for Life Sciences, University of Southampton, Southampton SO14 3ZH, UK. ; MUSERUM, Natural History Division, Havnevej 14, 7800 Skive, Denmark. ; Integrated Bioscience Program, University of Akron, Akron, Ohio 44325, USA. ; Mosasaur Ranch Museum, Lajitas, Texas 79852, USA. ; Roy M. Huffington Department of Earth Sciences, Southern Methodist University, Dallas, Texas 75275, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402224" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aquatic Organisms/*physiology ; *Biological Evolution ; Body Temperature Regulation ; Color ; *Extinction, Biological ; *Fossils ; Melanins/analysis ; Melanosis/*metabolism ; Melanosomes/chemistry ; Phylogeny ; Reptiles/*physiology ; Skin/chemistry ; *Skin Pigmentation ; Turtles/physiology
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  • 28
    Publication Date: 2014-03-07
    Description: A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA*DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046618/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046618/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haeusler, Aaron R -- Donnelly, Christopher J -- Periz, Goran -- Simko, Eric A J -- Shaw, Patrick G -- Kim, Min-Sik -- Maragakis, Nicholas J -- Troncoso, Juan C -- Pandey, Akhilesh -- Sattler, Rita -- Rothstein, Jeffrey D -- Wang, Jiou -- 5T32CA009110-36/CA/NCI NIH HHS/ -- NS07432/NS/NINDS NIH HHS/ -- NS085207/NS/NINDS NIH HHS/ -- P30 DK089502/DK/NIDDK NIH HHS/ -- P50 AG005146/AG/NIA NIH HHS/ -- P50AG05146/AG/NIA NIH HHS/ -- R01 NS074324/NS/NINDS NIH HHS/ -- R01 NS085207/NS/NINDS NIH HHS/ -- T32 CA009110/CA/NCI NIH HHS/ -- UL1 TR001079/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):195-200. doi: 10.1038/nature13124. Epub 2014 Mar 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA. ; 1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore, Maryland 21205, USA. ; Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA. ; Department of Pathology, Johns Hopkins University Baltimore, Maryland, 21205, USA. ; 1] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [3] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24598541" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/genetics ; B-Lymphocytes ; Base Sequence ; Cell Nucleolus/genetics/pathology ; DNA/genetics/metabolism ; DNA Repeat Expansion/*genetics ; Frontotemporal Dementia/genetics ; G-Quadruplexes ; HEK293 Cells ; Humans ; Models, Molecular ; Neurons ; Open Reading Frames/*genetics ; Phosphoproteins/metabolism ; RNA/biosynthesis/chemistry/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/metabolism ; Stress, Physiological ; Transcription, Genetic/genetics
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  • 29
    Publication Date: 2014-06-06
    Description: Previous studies have established that the folding, structure and function of membrane proteins are influenced by their lipid environments and that lipids can bind to specific sites, for example, in potassium channels. Fundamental questions remain however regarding the extent of membrane protein selectivity towards lipids. Here we report a mass spectrometry approach designed to determine the selectivity of lipid binding to membrane protein complexes. We investigate the mechanosensitive channel of large conductance (MscL) from Mycobacterium tuberculosis and aquaporin Z (AqpZ) and the ammonia channel (AmtB) from Escherichia coli, using ion mobility mass spectrometry (IM-MS), which reports gas-phase collision cross-sections. We demonstrate that folded conformations of membrane protein complexes can exist in the gas phase. By resolving lipid-bound states, we then rank bound lipids on the basis of their ability to resist gas phase unfolding and thereby stabilize membrane protein structure. Lipids bind non-selectively and with high avidity to MscL, all imparting comparable stability; however, the highest-ranking lipid is phosphatidylinositol phosphate, in line with its proposed functional role in mechanosensation. AqpZ is also stabilized by many lipids, with cardiolipin imparting the most significant resistance to unfolding. Subsequently, through functional assays we show that cardiolipin modulates AqpZ function. Similar experiments identify AmtB as being highly selective for phosphatidylglycerol, prompting us to obtain an X-ray structure in this lipid membrane-like environment. The 2.3 A resolution structure, when compared with others obtained without lipid bound, reveals distinct conformational changes that re-position AmtB residues to interact with the lipid bilayer. Our results demonstrate that resistance to unfolding correlates with specific lipid-binding events, enabling a distinction to be made between lipids that merely bind from those that modulate membrane protein structure and/or function. We anticipate that these findings will be important not only for defining the selectivity of membrane proteins towards lipids, but also for understanding the role of lipids in modulating protein function or drug binding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087533/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Laganowsky, Arthur -- Reading, Eamonn -- Allison, Timothy M -- Ulmschneider, Martin B -- Degiacomi, Matteo T -- Baldwin, Andrew J -- Robinson, Carol V -- 268851/European Research Council/International -- Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2014 Jun 5;510(7503):172-5. doi: 10.1038/nature13419.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 5QY, UK [2]. ; Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 5QY, UK. ; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24899312" target="_blank"〉PubMed〈/a〉
    Keywords: Ammonia/metabolism ; Apoproteins/chemistry/metabolism ; Aquaporins/chemistry/metabolism ; Bacterial Proteins/chemistry/metabolism ; Cardiolipins/chemistry/metabolism/pharmacology ; Cation Transport Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Escherichia coli/chemistry ; Escherichia coli Proteins/chemistry/metabolism ; Ion Channels/chemistry/metabolism ; Lipid Bilayers/chemistry ; Mass Spectrometry ; Membrane Lipids/chemistry/*metabolism/*pharmacology ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Mycobacterium tuberculosis/chemistry ; Phosphatidylglycerols/chemistry/metabolism/pharmacology ; Protein Conformation/drug effects ; Protein Folding/*drug effects ; Protein Stability/drug effects ; Protein Unfolding/drug effects ; Substrate Specificity
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  • 30
    Publication Date: 2014-09-26
    Description: The formation of branched lariat RNA is an evolutionarily conserved feature of splicing reactions for both group II and spliceosomal introns. The lariat is important for the fidelity of 5' splice-site selection and consists of a 2'-5' phosphodiester bond between a bulged adenosine and the 5' end of the intron. To gain insight into this ubiquitous intramolecular linkage, we determined the crystal structure of a eukaryotic group IIB intron in the lariat form at 3.7 A. This revealed that two tandem tetraloop-receptor interactions, eta-eta' and pi-pi', place domain VI in the core to position the lariat bond in the post-catalytic state. On the basis of structural and biochemical data, we propose that pi-pi' is a dynamic interaction that mediates the transition between the two steps of splicing, with eta-eta' serving an ancillary role. The structure also reveals a four-magnesium-ion cluster involved in both catalysis and positioning of the 5' end. Given the evolutionary relationship between group II and nuclear introns, it is likely that this active site configuration exists in the spliceosome as well.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robart, Aaron R -- Chan, Russell T -- Peters, Jessica K -- Rajashankar, Kanagalaghatta R -- Toor, Navtej -- 5R01GM102216/GM/NIGMS NIH HHS/ -- 5T32GM007240/GM/NIGMS NIH HHS/ -- 5T32GM008326/GM/NIGMS NIH HHS/ -- 8P41GM103403-10/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM102216/GM/NIGMS NIH HHS/ -- T32 GM007240/GM/NIGMS NIH HHS/ -- T32 GM008326/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Oct 9;514(7521):193-7. doi: 10.1038/nature13790. Epub 2014 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25252982" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Evolution, Molecular ; *Introns/genetics ; Magnesium/metabolism/pharmacology ; Models, Molecular ; *Nucleic Acid Conformation/drug effects ; *Phaeophyta/chemistry/genetics ; RNA Splicing/genetics ; Ribosome Subunits, Large/genetics ; Spliceosomes/chemistry
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  • 31
    Publication Date: 2014-09-05
    Description: SWEETs and their prokaryotic homologues are monosaccharide and disaccharide transporters that are present from Archaea to plants and humans. SWEETs play crucial roles in cellular sugar efflux processes: that is, in phloem loading, pollen nutrition and nectar secretion. Their bacterial homologues, which are called SemiSWEETs, are among the smallest known transporters. Here we show that SemiSWEET molecules, which consist of a triple-helix bundle, form symmetrical, parallel dimers, thereby generating the translocation pathway. Two SemiSWEET isoforms were crystallized, one in an apparently open state and one in an occluded state, indicating that SemiSWEETs and SWEETs are transporters that undergo rocking-type movements during the transport cycle. The topology of the triple-helix bundle is similar yet distinct to that of the basic building block of animal and plant major facilitator superfamily (MFS) transporters (for example, GLUTs and SUTs). This finding indicates two possibilities: that SWEETs and MFS transporters evolved from an ancestral triple-helix bundle or that the triple-helix bundle represents convergent evolution. In SemiSWEETs and SWEETs, two triple-helix bundles are arranged in a parallel configuration to produce the 6- and 6 + 1-transmembrane-helix pores, respectively. In the 12-transmembrane-helix MFS transporters, four triple-helix bundles are arranged into an alternating antiparallel configuration, resulting in a much larger 2 x 2 triple-helix bundle forming the pore. Given the similarity of SemiSWEETs and SWEETs to PQ-loop amino acid transporters and to mitochondrial pyruvate carriers (MPCs), the structures characterized here may also be relevant to other transporters in the MtN3 clan. The insight gained from the structures of these transporters and from the analysis of mutations of conserved residues will improve the understanding of the transport mechanism, as well as allow comparative studies of the different superfamilies involved in sugar transport and the evolution of transporters in general.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300204/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300204/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Yan -- Tao, Yuyong -- Cheung, Lily S -- Fan, Chao -- Chen, Li-Qing -- Xu, Sophia -- Perry, Kay -- Frommer, Wolf B -- Feng, Liang -- P41 GM103403/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):448-52. doi: 10.1038/nature13670. Epub 2014 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, 279 Campus Drive, Stanford University School of Medicine, Stanford, California 94305, USA [2]. ; 1] Department of Plant Biology, Carnegie Institution for Science, 260 Panama Street, Stanford, California 94305, USA [2]. ; Department of Molecular and Cellular Physiology, 279 Campus Drive, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Plant Biology, Carnegie Institution for Science, 260 Panama Street, Stanford, California 94305, USA. ; Department of Biology, Stanford University, Stanford, California 94305, USA. ; NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Building 436E, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA. ; 1] Department of Plant Biology, Carnegie Institution for Science, 260 Panama Street, Stanford, California 94305, USA [2] Department of Biology, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186729" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/chemistry ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Evolution, Molecular ; Glucose/metabolism ; Leptospira/*chemistry/genetics ; Models, Molecular ; Monosaccharide Transport Proteins/*chemistry/genetics/metabolism ; Movement ; Protein Conformation ; Protein Multimerization ; Structure-Activity Relationship ; Vibrio/*chemistry
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  • 32
    Publication Date: 2014-03-29
    Description: The light-harvesting core antenna (LH1) and the reaction centre (RC) of purple photosynthetic bacteria form a supramolecular complex (LH1-RC) to use sunlight energy in a highly efficient manner. Here we report the first near-atomic structure, to our knowledge, of a LH1-RC complex, namely that of a Ca(2+)-bound complex from Thermochromatium tepidum, which reveals detailed information on the arrangement and interactions of the protein subunits and the cofactors. The RC is surrounded by 16 heterodimers of the LH1 alphabeta-subunit that form a completely closed structure. The Ca(2+) ions are located at the periplasmic side of LH1. Thirty-two bacteriochlorophyll and 16 spirilloxanthin molecules in the LH1 ring form an elliptical assembly. The geometries of the pigment assembly involved in the absorption characteristics of the bacteriochlorophyll in LH1 and excitation energy transfer among the pigments are reported. In addition, possible ubiquinone channels in the closed LH1 complex are proposed based on the atomic structure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Niwa, Satomi -- Yu, Long-Jiang -- Takeda, Kazuki -- Hirano, Yu -- Kawakami, Tomoaki -- Wang-Otomo, Zheng-Yu -- Miki, Kunio -- England -- Nature. 2014 Apr 10;508(7495):228-32. doi: 10.1038/nature13197. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan [2]. ; 1] Faculty of Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan [2]. ; Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. ; Faculty of Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670637" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriochlorophylls/chemistry/metabolism ; Calcium/metabolism ; Chromatiaceae/*chemistry ; Coenzymes/chemistry/metabolism ; Crystallography, X-Ray ; Light-Harvesting Protein Complexes/*chemistry/metabolism ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Ubiquinone/metabolism ; Xanthophylls/chemistry/metabolism
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  • 33
    Publication Date: 2014-06-12
    Description: Eucalypts are the world's most widely planted hardwood trees. Their outstanding diversity, adaptability and growth have made them a global renewable resource of fibre and energy. We sequenced and assembled 〉94% of the 640-megabase genome of Eucalyptus grandis. Of 36,376 predicted protein-coding genes, 34% occur in tandem duplications, the largest proportion thus far in plant genomes. Eucalyptus also shows the highest diversity of genes for specialized metabolites such as terpenes that act as chemical defence and provide unique pharmaceutical oils. Genome sequencing of the E. grandis sister species E. globulus and a set of inbred E. grandis tree genomes reveals dynamic genome evolution and hotspots of inbreeding depression. The E. grandis genome is the first reference for the eudicot order Myrtales and is placed here sister to the eurosids. This resource expands our understanding of the unique biology of large woody perennials and provides a powerful tool to accelerate comparative biology, breeding and biotechnology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Myburg, Alexander A -- Grattapaglia, Dario -- Tuskan, Gerald A -- Hellsten, Uffe -- Hayes, Richard D -- Grimwood, Jane -- Jenkins, Jerry -- Lindquist, Erika -- Tice, Hope -- Bauer, Diane -- Goodstein, David M -- Dubchak, Inna -- Poliakov, Alexandre -- Mizrachi, Eshchar -- Kullan, Anand R K -- Hussey, Steven G -- Pinard, Desre -- van der Merwe, Karen -- Singh, Pooja -- van Jaarsveld, Ida -- Silva-Junior, Orzenil B -- Togawa, Roberto C -- Pappas, Marilia R -- Faria, Danielle A -- Sansaloni, Carolina P -- Petroli, Cesar D -- Yang, Xiaohan -- Ranjan, Priya -- Tschaplinski, Timothy J -- Ye, Chu-Yu -- Li, Ting -- Sterck, Lieven -- Vanneste, Kevin -- Murat, Florent -- Soler, Marcal -- Clemente, Helene San -- Saidi, Naijib -- Cassan-Wang, Hua -- Dunand, Christophe -- Hefer, Charles A -- Bornberg-Bauer, Erich -- Kersting, Anna R -- Vining, Kelly -- Amarasinghe, Vindhya -- Ranik, Martin -- Naithani, Sushma -- Elser, Justin -- Boyd, Alexander E -- Liston, Aaron -- Spatafora, Joseph W -- Dharmwardhana, Palitha -- Raja, Rajani -- Sullivan, Christopher -- Romanel, Elisson -- Alves-Ferreira, Marcio -- Kulheim, Carsten -- Foley, William -- Carocha, Victor -- Paiva, Jorge -- Kudrna, David -- Brommonschenkel, Sergio H -- Pasquali, Giancarlo -- Byrne, Margaret -- Rigault, Philippe -- Tibbits, Josquin -- Spokevicius, Antanas -- Jones, Rebecca C -- Steane, Dorothy A -- Vaillancourt, Rene E -- Potts, Brad M -- Joubert, Fourie -- Barry, Kerrie -- Pappas, Georgios J -- Strauss, Steven H -- Jaiswal, Pankaj -- Grima-Pettenati, Jacqueline -- Salse, Jerome -- Van de Peer, Yves -- Rokhsar, Daniel S -- Schmutz, Jeremy -- England -- Nature. 2014 Jun 19;510(7505):356-62. doi: 10.1038/nature13308. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genetics, Forestry and Agricultural Biotechnology Institute (FABI), University of Pretoria, Private bag X20, Pretoria 0028, South Africa [2] Genomics Research Institute (GRI), University of Pretoria, Private bag X20, Pretoria 0028, South Africa. ; 1] Laboratorio de Genetica Vegetal, EMBRAPA Recursos Geneticos e Biotecnologia, EPQB Final W5 Norte, 70770-917 Brasilia, Brazil [2] Programa de Ciencias Genomicas e Biotecnologia - Universidade Catolica de Brasilia SGAN 916, 70790-160 Brasilia, Brazil. ; 1] US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA [2] Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. ; US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA. ; HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35801, USA. ; Bioinformatics and Computational Biology Unit, Department of Biochemistry, University of Pretoria, Pretoria, Private bag X20, Pretoria 0028, South Africa. ; Laboratorio de Bioinformatica, EMBRAPA Recursos Geneticos e Biotecnologia, EPQB Final W5 Norte, 70770-917 Brasilia, Brazil. ; Laboratorio de Genetica Vegetal, EMBRAPA Recursos Geneticos e Biotecnologia, EPQB Final W5 Norte, 70770-917 Brasilia, Brazil. ; Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. ; Department of Plant Biotechnology and Bioinformatics (VIB), Ghent University, Technologiepark 927, B-9000 Ghent, Belgium. ; INRA/UBP UMR 1095, 5 Avenue de Beaulieu, 63100 Clermont Ferrand, France. ; Laboratoire de Recherche en Sciences Vegetales, UMR 5546, Universite Toulouse III, UPS, CNRS, BP 42617, 31326 Castanet Tolosan, France. ; 1] Bioinformatics and Computational Biology Unit, Department of Biochemistry, University of Pretoria, Pretoria, Private bag X20, Pretoria 0028, South Africa [2] Department of Botany, University of British Columbia, 3529-6270 University Blvd, Vancouver V6T 1Z4, Canada. ; Evolutionary Bioinformatics, Institute for Evolution and Biodiversity, University of Muenster, Huefferstrasse 1, D-48149, Muenster, Germany. ; 1] Evolutionary Bioinformatics, Institute for Evolution and Biodiversity, University of Muenster, Huefferstrasse 1, D-48149, Muenster, Germany [2] Department of Bioinformatics, Institute for Computer Science, University of Duesseldorf, Universitatsstrasse 1, 40225 Dusseldorf, Germany. ; Department of Forest Ecosystems and Society, Oregon State University, Corvallis, Oregon 97331, USA. ; 1] Department of Botany and Plant Pathology, Oregon State University, 2082-Cordley Hall, Corvallis, Oregon 97331, USA [2] Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97331, USA. ; Department of Botany and Plant Pathology, Oregon State University, 2082-Cordley Hall, Corvallis, Oregon 97331, USA. ; Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97331, USA. ; 1] Laboratorio de Biologia Evolutiva Teorica e Aplicada, Departamento de Genetica, Universidade Federal do Rio de Janeiro (UFRJ), Av. Prof. Rodolpho Paulo Rocco, 21949900 Rio de Janeiro, Brazil [2] Departamento de Biotecnologia, Escola de Engenharia de Lorena-Universidade de Sao Paulo (EEL-USP), CP116, 12602-810, Lorena-SP, Brazil [3] Laboratorio de Genetica Molecular Vegetal (LGMV), Departamento de Genetica, Universidade Federal do Rio de Janeiro (UFRJ), Av. Prof. Rodolpho Paulo Rocco, 21949900 Rio de Janeiro, Brazil. ; Laboratorio de Genetica Molecular Vegetal (LGMV), Departamento de Genetica, Universidade Federal do Rio de Janeiro (UFRJ), Av. Prof. Rodolpho Paulo Rocco, 21949900 Rio de Janeiro, Brazil. ; Research School of Biology, Australian National University, Canberra 0200, Australia. ; 1] Laboratoire de Recherche en Sciences Vegetales, UMR 5546, Universite Toulouse III, UPS, CNRS, BP 42617, 31326 Castanet Tolosan, France [2] IICT/MNE; Palacio Burnay - Rua da Junqueira, 30, 1349-007 Lisboa, Portugal [3] IBET/ITQB, Av. Republica, Quinta do Marques, 2781-901 Oeiras, Portugal. ; 1] IICT/MNE; Palacio Burnay - Rua da Junqueira, 30, 1349-007 Lisboa, Portugal [2] IBET/ITQB, Av. Republica, Quinta do Marques, 2781-901 Oeiras, Portugal. ; Arizona Genomics Institute, University of Arizona, Tucson, Arizona 85721, USA. ; Dep. de Fitopatologia, Universidade Federal de Vicosa, Vicosa 36570-000, Brazil. ; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Brazil. ; Science and Conservation Division, Department of Parks and Wildlife, Locked Bag 104, Bentley Delivery Centre, Western Australia 6983, Australia. ; GYDLE, 1363 av. Maguire, suite 301, Quebec, Quebec G1T 1Z2, Canada. ; Department of Environment and Primary Industries, Victorian Government, Melbourne, Victoria 3085, Australia. ; Melbourne School of Land and Environment, University of Melbourne, Melbourne, Victoria 3010, Australia. ; School of Biological Sciences and National Centre for Future Forest Industries, University of Tasmania, Private Bag 55, Hobart, Tasmania 7001, Australia. ; 1] School of Biological Sciences and National Centre for Future Forest Industries, University of Tasmania, Private Bag 55, Hobart, Tasmania 7001, Australia [2] Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland 4558, Australia. ; 1] Genomics Research Institute (GRI), University of Pretoria, Private bag X20, Pretoria 0028, South Africa [2] Bioinformatics and Computational Biology Unit, Department of Biochemistry, University of Pretoria, Pretoria, Private bag X20, Pretoria 0028, South Africa. ; Departamento de Biologia Celular, Universidade de Brasilia, Brasilia 70910-900, Brazil. ; 1] Genomics Research Institute (GRI), University of Pretoria, Private bag X20, Pretoria 0028, South Africa [2] Department of Plant Biotechnology and Bioinformatics (VIB), Ghent University, Technologiepark 927, B-9000 Ghent, Belgium. ; 1] US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA [2] HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919147" target="_blank"〉PubMed〈/a〉
    Keywords: Eucalyptus/classification/*genetics ; Evolution, Molecular ; Genetic Variation ; *Genome, Plant ; Inbreeding ; Phylogeny
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  • 34
    Publication Date: 2014-07-22
    Description: Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162811/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Bo -- Qiu, Bo -- Lee, David S M -- Walton, Zandra E -- Ochocki, Joshua D -- Mathew, Lijoy K -- Mancuso, Anthony -- Gade, Terence P F -- Keith, Brian -- Nissim, Itzhak -- Simon, M Celeste -- CA104838/CA/NCI NIH HHS/ -- DK053761/DK/NIDDK NIH HHS/ -- F30 CA177106/CA/NCI NIH HHS/ -- F32 CA192758/CA/NCI NIH HHS/ -- P01 CA104838/CA/NCI NIH HHS/ -- P30 CA016520/CA/NCI NIH HHS/ -- R01 DK053761/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 11;513(7517):251-5. doi: 10.1038/nature13557. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Pediatrics, Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA [3] Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043030" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carcinoma, Renal Cell/*enzymology/genetics/physiopathology ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Disease Progression ; Epithelial Cells/metabolism ; Fructose-Bisphosphatase/chemistry/genetics/*metabolism ; Glycolysis ; Humans ; Kidney Neoplasms/*enzymology/genetics/physiopathology ; Models, Molecular ; NADP/metabolism ; Protein Structure, Tertiary ; Swine
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  • 35
    Publication Date: 2014-07-22
    Description: Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 A resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca(2+) influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Srivastava, Ankita -- Yano, Jason -- Hirozane, Yoshihiko -- Kefala, Georgia -- Gruswitz, Franz -- Snell, Gyorgy -- Lane, Weston -- Ivetac, Anthony -- Aertgeerts, Kathleen -- Nguyen, Jasmine -- Jennings, Andy -- Okada, Kengo -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):124-7. doi: 10.1038/nature13494. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2]. ; Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. ; Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA. ; 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2] Beryllium, Membrane Protein Sciences, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA (F.G.); Dart Neuroscience, 12278 Scripps Summit Drive, San Diego, California 92131, USA (K.A. and J.N.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043059" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Benzofurans/*chemistry/metabolism/*pharmacology ; Binding Sites ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/drug therapy ; *Drug Partial Agonism ; Humans ; Ligands ; Lipid Bilayers/metabolism ; Models, Molecular ; Receptors, G-Protein-Coupled/*agonists/*chemistry/metabolism ; Structural Homology, Protein ; Sulfones/*chemistry/metabolism/*pharmacology ; Surface Properties
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  • 36
    Publication Date: 2014-07-06
    Description: Discoveries of bird-like theropod dinosaurs and basal avialans in recent decades have helped to put the iconic 'Urvogel' Archaeopteryx into context and have yielded important new data on the origin and early evolution of feathers. However, the biological context under which pennaceous feathers evolved is still debated. Here we describe a new specimen of Archaeopteryx with extensive feather preservation, not only on the wings and tail, but also on the body and legs. The new specimen shows that the entire body was covered in pennaceous feathers, and that the hindlimbs had long, symmetrical feathers along the tibiotarsus but short feathers on the tarsometatarsus. Furthermore, the wing plumage demonstrates that several recent interpretations are problematic. An analysis of the phylogenetic distribution of pennaceous feathers on the tail, hindlimb and arms of advanced maniraptorans and basal avialans strongly indicates that these structures evolved in a functional context other than flight, most probably in relation to display, as suggested by some previous studies. Pennaceous feathers thus represented an exaptation and were later, in several lineages and following different patterns, recruited for aerodynamic functions. This indicates that the origin of flight in avialans was more complex than previously thought and might have involved several convergent achievements of aerial abilities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Foth, Christian -- Tischlinger, Helmut -- Rauhut, Oliver W M -- England -- Nature. 2014 Jul 3;511(7507):79-82. doi: 10.1038/nature13467.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Staatliche Naturwissenschaftliche Sammlungen Bayerns, Bayerische Staatssammlung fur Palaontologie und Geologie, Richard-Wagner-Strasse 10, 80333 Munich, Germany [2] Department of Earth and Environmental Sciences and GeoBioCenter, Ludwig-Maximilians-Universitat Munchen, Richard-Wagner-Strasse 10, 80333 Munich, Germany. ; Tannenweg 16, 85134 Stammham, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990749" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Birds/anatomy & histology ; Dinosaurs/*anatomy & histology ; Feathers/*anatomy & histology ; *Fossils ; Germany ; Hindlimb/anatomy & histology ; Phylogeny ; Skeleton ; Tail/anatomy & histology ; Wings, Animal/anatomy & histology
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  • 37
    Publication Date: 2014-08-22
    Description: Liquid water has been known to occur beneath the Antarctic ice sheet for more than 40 years, but only recently have these subglacial aqueous environments been recognized as microbial ecosystems that may influence biogeochemical transformations on a global scale. Here we present the first geomicrobiological description of water and surficial sediments obtained from direct sampling of a subglacial Antarctic lake. Subglacial Lake Whillans (SLW) lies beneath approximately 800 m of ice on the lower portion of the Whillans Ice Stream (WIS) in West Antarctica and is part of an extensive and evolving subglacial drainage network. The water column of SLW contained metabolically active microorganisms and was derived primarily from glacial ice melt with solute sources from lithogenic weathering and a minor seawater component. Heterotrophic and autotrophic production data together with small subunit ribosomal RNA gene sequencing and biogeochemical data indicate that SLW is a chemosynthetically driven ecosystem inhabited by a diverse assemblage of bacteria and archaea. Our results confirm that aquatic environments beneath the Antarctic ice sheet support viable microbial ecosystems, corroborating previous reports suggesting that they contain globally relevant pools of carbon and microbes that can mobilize elements from the lithosphere and influence Southern Ocean geochemical and biological systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christner, Brent C -- Priscu, John C -- Achberger, Amanda M -- Barbante, Carlo -- Carter, Sasha P -- Christianson, Knut -- Michaud, Alexander B -- Mikucki, Jill A -- Mitchell, Andrew C -- Skidmore, Mark L -- Vick-Majors, Trista J -- WISSARD Science Team -- England -- Nature. 2014 Aug 21;512(7514):310-3. doi: 10.1038/nature13667.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA. ; Department of Land Resources and Environmental Science, Montana State University, Bozeman, Montana 59717, USA. ; Institute for the Dynamics of Environmental Processes - CNR, Venice, and Department of Environmental Sciences, Informatics and Statistics, Ca'Foscari University of Venice, Venice 30123, Italy. ; Institute of Geophysics and Planetary Physics, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA. ; 1] Physics Department, St Olaf College, Northfield, Minnesota 55057, USA [2] Courant Institute of Mathematical Sciences, New York University, New York, New York 10012, USA (K.C.). ; Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996, USA. ; Department of Geography and Earth Sciences, Aberystwyth University, Aberystwyth SY23 3DB, UK. ; Department of Earth Science, Montana State University, Bozeman, Montana 59717, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25143114" target="_blank"〉PubMed〈/a〉
    Keywords: Antarctic Regions ; Aquatic Organisms/classification/genetics/*isolation & purification/metabolism ; Archaea/classification/genetics/isolation & purification/metabolism ; Bacteria/classification/genetics/isolation & purification/metabolism ; Carbon/metabolism ; *Ecosystem ; Geologic Sediments/chemistry/microbiology ; *Ice Cover/chemistry ; Lakes/chemistry/*microbiology ; Oceans and Seas ; Phylogeny
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 38
    Publication Date: 2014-09-16
    Description: The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and (1)H-(15)N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351747/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Chao -- Liu, Degang -- Li, Liwei -- Wempe, Michael F -- Guin, Sunny -- Khanna, May -- Meier, Jeremy -- Hoffman, Brenton -- Owens, Charles -- Wysoczynski, Christina L -- Nitz, Matthew D -- Knabe, William E -- Ahmed, Mansoor -- Brautigan, David L -- Paschal, Bryce M -- Schwartz, Martin A -- Jones, David N M -- Ross, David -- Meroueh, Samy O -- Theodorescu, Dan -- CA075115/CA/NCI NIH HHS/ -- CA091846/CA/NCI NIH HHS/ -- CA104106/CA/NCI NIH HHS/ -- GM47214/GM/NIGMS NIH HHS/ -- P01 CA104106/CA/NCI NIH HHS/ -- P30 CA044579/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P50 CA091846/CA/NCI NIH HHS/ -- R01 CA075115/CA/NCI NIH HHS/ -- R01 CA143971/CA/NCI NIH HHS/ -- T32 GM007635/GM/NIGMS NIH HHS/ -- UL1 TR001082/TR/NCATS NIH HHS/ -- UL1TR001082/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):443-7. doi: 10.1038/nature13713. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA. ; Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045, USA. ; Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA. ; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Department of Cardiology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Cell Biology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [2] Department of Chemistry and Chemical Biology, Indiana University - Purdue University, Indianapolis, Indiana 46202, USA. ; 1] Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA [2] Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA [3] University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219851" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/metabolism ; Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Computer Simulation ; *Drug Screening Assays, Antitumor ; Female ; GTPase-Activating Proteins/metabolism ; Humans ; Mice ; Models, Molecular ; *Molecular Targeted Therapy ; Neoplasms/drug therapy/enzymology/metabolism/pathology ; Protein Binding/drug effects ; Signal Transduction/drug effects ; Small Molecule Libraries/*chemistry/*pharmacology ; Substrate Specificity ; Xenograft Model Antitumor Assays ; ral GTP-Binding Proteins/*antagonists & inhibitors/chemistry/metabolism ; ras Proteins/metabolism
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  • 39
    Publication Date: 2014-06-12
    Description: Ligation of tRNAs with their cognate amino acids, by aminoacyl-tRNA synthetases, establishes the genetic code. Throughout evolution, tRNA(Ala) selection by alanyl-tRNA synthetase (AlaRS) has depended predominantly on a single wobble base pair in the acceptor stem, G3*U70, mainly on the kcat level. Here we report the crystal structures of an archaeal AlaRS in complex with tRNA(Ala) with G3*U70 and its A3*U70 variant. AlaRS interacts with both the minor- and the major-groove sides of G3*U70, widening the major groove. The geometry difference between G3*U70 and A3*U70 is transmitted along the acceptor stem to the 3'-CCA region. Thus, the 3'-CCA region of tRNA(Ala) with G3*U70 is oriented to the reactive route that reaches the active site, whereas that of the A3*U70 variant is folded back into the non-reactive route. This novel mechanism enables the single wobble pair to dominantly determine the specificity of tRNA selection, by an approximate 100-fold difference in kcat.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323281/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323281/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naganuma, Masahiro -- Sekine, Shun-ichi -- Chong, Yeeting Esther -- Guo, Min -- Yang, Xiang-Lei -- Gamper, Howard -- Hou, Ya-Ming -- Schimmel, Paul -- Yokoyama, Shigeyuki -- GM015539/GM/NIGMS NIH HHS/ -- GM023562/GM/NIGMS NIH HHS/ -- NS085092/NS/NINDS NIH HHS/ -- R01 GM015539/GM/NIGMS NIH HHS/ -- R01 GM023562/GM/NIGMS NIH HHS/ -- R01 GM100136/GM/NIGMS NIH HHS/ -- R01 NS085092/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):507-11. doi: 10.1038/nature13440. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] aTyr Pharma, 3545 John Hopkins Court, San Diego, California 92121, USA (Y.E.C.); Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA (M.G.). ; The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; 1] The Skaggs Institute for Chemical Biology and the Department of Cell and Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] The Scripps Florida Research Institute, 130 Scripps Way, 3B3 Jupiter, Florida 33458-5284, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919148" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/analogs & derivatives/chemistry ; Alanine-tRNA Ligase/*chemistry ; Archaeoglobus fulgidus/*enzymology/*genetics ; *Base Pairing ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Models, Molecular ; RNA, Transfer, Ala/*chemistry/*genetics ; Substrate Specificity ; *Transfer RNA Aminoacylation
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  • 40
    Publication Date: 2014-08-15
    Description: Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structure of a mammalian Cys-loop receptor, the mouse serotonin 5-HT3 receptor, at 3.5 A resolution. The structure of the proteolysed receptor, made up of two fragments and comprising part of the intracellular domain, was determined in complex with stabilizing nanobodies. The extracellular domain reveals the detailed anatomy of the neurotransmitter binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6 A constriction. In the intracellular domain, a bundle of five intracellular helices creates a closed vestibule where lateral portals are obstructed by loops. This 5-HT3 receptor structure, revealing part of the intracellular domain, expands the structural basis for understanding the operating mechanism of mammalian Cys-loop receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hassaine, Gherici -- Deluz, Cedric -- Grasso, Luigino -- Wyss, Romain -- Tol, Menno B -- Hovius, Ruud -- Graff, Alexandra -- Stahlberg, Henning -- Tomizaki, Takashi -- Desmyter, Aline -- Moreau, Christophe -- Li, Xiao-Dan -- Poitevin, Frederic -- Vogel, Horst -- Nury, Hugues -- England -- Nature. 2014 Aug 21;512(7514):276-81. doi: 10.1038/nature13552. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2] [3] Theranyx, 163 Avenue de Luminy, 13288 Marseille, France. ; 1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2]. ; Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland. ; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, CH-4058 Basel, Switzerland. ; Swiss Light Source, Paul Scherrer Institute, CH-5234 Villigen, Switzerland. ; Architecture et Fonction des Macromolecules Biologiques, CNRS UMR 7257 and Universite Aix-Marseille, F-13288 Marseille, France. ; 1] Universite Grenoble Alpes, IBS, F-38000 Grenoble, France [2] CNRS, IBS, F-38000 Grenoble, France [3] CEA, DSV, IBS, F-38000 Grenoble, France. ; Laboratory of Biomolecular Research, Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Unite de Dynamique Structurale des Macromolecules, Institut Pasteur, CNRS UMR3528, F-75015 Paris, France. ; 1] Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland [2] Universite Grenoble Alpes, IBS, F-38000 Grenoble, France [3] CNRS, IBS, F-38000 Grenoble, France [4] CEA, DSV, IBS, F-38000 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119048" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Crystallography, X-Ray ; Mice ; Models, Molecular ; Molecular Sequence Data ; Neurotransmitter Agents/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Receptors, Serotonin, 5-HT3/*chemistry/metabolism
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  • 41
    Publication Date: 2014-07-22
    Description: In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fischer, Eric S -- Bohm, Kerstin -- Lydeard, John R -- Yang, Haidi -- Stadler, Michael B -- Cavadini, Simone -- Nagel, Jane -- Serluca, Fabrizio -- Acker, Vincent -- Lingaraju, Gondichatnahalli M -- Tichkule, Ritesh B -- Schebesta, Michael -- Forrester, William C -- Schirle, Markus -- Hassiepen, Ulrich -- Ottl, Johannes -- Hild, Marc -- Beckwith, Rohan E J -- Harper, J Wade -- Jenkins, Jeremy L -- Thoma, Nicolas H -- AG011085/AG/NIA NIH HHS/ -- R01 AG011085/AG/NIA NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):49-53. doi: 10.1038/nature13527. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland. ; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland [3] Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043012" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; DNA-Binding Proteins/agonists/antagonists & inhibitors/chemistry/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/agonists/antagonists & inhibitors/chemistry/metabolism ; Peptide Hydrolases/*chemistry/metabolism ; Protein Binding ; Structure-Activity Relationship ; Substrate Specificity ; Thalidomide/analogs & derivatives/*chemistry/metabolism ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/antagonists & inhibitors/*chemistry/metabolism
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  • 42
    Publication Date: 2014-04-04
    Description: Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huber, Kilian V M -- Salah, Eidarus -- Radic, Branka -- Gridling, Manuela -- Elkins, Jonathan M -- Stukalov, Alexey -- Jemth, Ann-Sofie -- Gokturk, Camilla -- Sanjiv, Kumar -- Stromberg, Kia -- Pham, Therese -- Berglund, Ulrika Warpman -- Colinge, Jacques -- Bennett, Keiryn L -- Loizou, Joanna I -- Helleday, Thomas -- Knapp, Stefan -- Superti-Furga, Giulio -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- F 4711/Austrian Science Fund FWF/Austria -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Apr 10;508(7495):222-7. doi: 10.1038/nature13194. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17121 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695225" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoquinolines/pharmacology ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Colonic Neoplasms/drug therapy/genetics/pathology ; Crystallization ; DNA Breaks, Single-Stranded/drug effects ; DNA Repair ; DNA Repair Enzymes/*antagonists & inhibitors/biosynthesis/chemistry/*metabolism ; Disease Models, Animal ; Female ; Homeostasis/drug effects ; Humans ; Mice ; Mice, SCID ; Models, Molecular ; Nucleotides/metabolism ; Phosphoric Monoester Hydrolases/*antagonists & ; inhibitors/biosynthesis/chemistry/*metabolism ; Protein Conformation ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Proteomics ; Proto-Oncogene Proteins/genetics ; Pyrazoles/chemistry/*pharmacology ; Pyridines/chemistry/*pharmacology ; Substrate Specificity ; Xenograft Model Antitumor Assays ; ras Proteins/genetics
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  • 43
    Publication Date: 2014-05-03
    Description: The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, is one of the most prominent clinical drug targets for inhibition of platelet aggregation. Although mutagenesis and modelling studies of the P2Y12R provided useful insights into ligand binding, the agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here we report the structures of the human P2Y12R in complex with the full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 A resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 A resolution. These structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283), reveal striking conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions. Further analysis of these changes provides insight into a distinct ligand binding landscape in the delta-group of class A G-protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing questions surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example, to our knowledge, of a GPCR in which agonist access to the binding pocket requires large-scale rearrangements in the highly malleable extracellular region, the structural and docking studies will therefore provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128917/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jin -- Zhang, Kaihua -- Gao, Zhan-Guo -- Paoletta, Silvia -- Zhang, Dandan -- Han, Gye Won -- Li, Tingting -- Ma, Limin -- Zhang, Wenru -- Muller, Christa E -- Yang, Huaiyu -- Jiang, Hualiang -- Cherezov, Vadim -- Katritch, Vsevolod -- Jacobson, Kenneth A -- Stevens, Raymond C -- Wu, Beili -- Zhao, Qiang -- R01 AI100604/AI/NIAID NIH HHS/ -- R01AI100604/AI/NIAID NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):119-22. doi: 10.1038/nature13288.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China [2]. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; PharmaCenter Bonn, University of Bonn, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24784220" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/*analogs & derivatives/chemistry/metabolism ; Adenosine Triphosphate/*analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Humans ; Ligands ; Models, Molecular ; Niacin/analogs & derivatives/chemistry/metabolism ; Protein Conformation ; Purinergic P2Y Receptor Agonists/*chemistry/metabolism ; Purinergic P2Y Receptor Antagonists/chemistry/metabolism ; Receptors, Purinergic P2Y12/*chemistry/metabolism ; Substrate Specificity ; Sulfonamides/chemistry/metabolism ; Thionucleotides/*chemistry/metabolism
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  • 44
    Publication Date: 2014-03-29
    Description: Bacterial type IV secretion systems translocate virulence factors into eukaryotic cells, distribute genetic material between bacteria and have shown potential as a tool for the genetic modification of human cells. Given the complex choreography of the substrate through the secretion apparatus, the molecular mechanism of the type IV secretion system has proved difficult to dissect in the absence of structural data for the entire machinery. Here we use electron microscopy to reconstruct the type IV secretion system encoded by the Escherichia coli R388 conjugative plasmid. We show that eight proteins assemble in an intricate stoichiometric relationship to form an approximately 3 megadalton nanomachine that spans the entire cell envelope. The structure comprises an outer membrane-associated core complex connected by a central stalk to a substantial inner membrane complex that is dominated by a battery of 12 VirB4 ATPase subunits organized as side-by-side hexameric barrels. Our results show a secretion system with markedly different architecture, and consequently mechanism, to other known bacterial secretion systems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998870/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Low, Harry H -- Gubellini, Francesca -- Rivera-Calzada, Angel -- Braun, Nathalie -- Connery, Sarah -- Dujeancourt, Annick -- Lu, Fang -- Redzej, Adam -- Fronzes, Remi -- Orlova, Elena V -- Waksman, Gabriel -- 079605/Wellcome Trust/United Kingdom -- 098302/Wellcome Trust/United Kingdom -- MR/K012401/1/Medical Research Council/United Kingdom -- England -- Nature. 2014 Apr 24;508(7497):550-3. doi: 10.1038/nature13081. Epub 2014 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Structural and Molecular Biology, University College London and Birkbeck College, Malet Street, London WC1E 7HX, UK [2] [3]. ; 1] Institut Pasteur, G5 Biologie structurale de la secretion bacterienne and UMR 3528-CNRS, 25 rue du Docteur Roux, 75015 Paris, France [2]. ; Institute of Structural and Molecular Biology, University College London and Birkbeck College, Malet Street, London WC1E 7HX, UK. ; Institut Pasteur, G5 Biologie structurale de la secretion bacterienne and UMR 3528-CNRS, 25 rue du Docteur Roux, 75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670658" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/genetics/metabolism/ultrastructure ; *Bacterial Secretion Systems/genetics ; Cell Membrane/metabolism ; Escherichia coli/*chemistry/cytology/genetics/*ultrastructure ; Escherichia coli Proteins/chemistry/isolation & ; purification/metabolism/ultrastructure ; Microscopy, Electron ; Models, Molecular ; Multiprotein Complexes/chemistry/genetics/metabolism/ultrastructure
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  • 45
    Publication Date: 2014-01-28
    Description: H2A.Z is an essential histone variant implicated in the regulation of key nuclear events. However, the metazoan chaperones responsible for H2A.Z deposition and its removal from chromatin remain unknown. Here we report the identification and characterization of the human protein ANP32E as a specific H2A.Z chaperone. We show that ANP32E is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. ANP32E interacts with a short region of the docking domain of H2A.Z through a new motif termed H2A.Z interacting domain (ZID). The 1.48 A resolution crystal structure of the complex formed between the ANP32E-ZID and the H2A.Z/H2B dimer and biochemical data support an underlying molecular mechanism for H2A.Z/H2B eviction from the nucleosome and its stabilization by ANP32E through a specific extension of the H2A.Z carboxy-terminal alpha-helix. Finally, analysis of H2A.Z localization in ANP32E(-/-) cells by chromatin immunoprecipitation followed by sequencing shows genome-wide enrichment, redistribution and accumulation of H2A.Z at specific chromatin control regions, in particular at enhancers and insulators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obri, Arnaud -- Ouararhni, Khalid -- Papin, Christophe -- Diebold, Marie-Laure -- Padmanabhan, Kiran -- Marek, Martin -- Stoll, Isabelle -- Roy, Ludovic -- Reilly, Patrick T -- Mak, Tak W -- Dimitrov, Stefan -- Romier, Christophe -- Hamiche, Ali -- England -- Nature. 2014 Jan 30;505(7485):648-53. doi: 10.1038/nature12922. Epub 2014 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Departement de Genomique Fonctionnelle et Cancer, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France [2]. ; Departement de Biologie Structurale Integrative, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France. ; Equipe labelisee Ligue contre le Cancer, INSERM/Universite Joseph Fourier , Institut Albert Bonniot, U823, Site Sante-BP 170, 38042 Grenoble Cedex 9, France. ; Departement de Genomique Fonctionnelle et Cancer, Institut de Genetique et Biologie Moleculaire et Cellulaire (IGBMC), Universite de Strasbourg, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Illkirch Cedex, France. ; Laboratory of Inflammation Biology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore. ; 1] Laboratory of Inflammation Biology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore [2] The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463511" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Line ; Cell Nucleus/chemistry/metabolism ; Chromatin/*chemistry/genetics/*metabolism ; Chromatin Immunoprecipitation ; Crystallography, X-Ray ; DNA/genetics/metabolism ; Genome, Human/genetics ; Histones/chemistry/isolation & purification/*metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/chemistry/*metabolism ; Nucleosomes/chemistry/metabolism ; Phosphoproteins/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Substrate Specificity
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  • 46
    Publication Date: 2014-03-29
    Description: P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation, and several antithrombotic drugs targeting P2Y12R--including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor--have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. Here we report the 2.6 A resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174307/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174307/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Kaihua -- Zhang, Jin -- Gao, Zhan-Guo -- Zhang, Dandan -- Zhu, Lan -- Han, Gye Won -- Moss, Steven M -- Paoletta, Silvia -- Kiselev, Evgeny -- Lu, Weizhen -- Fenalti, Gustavo -- Zhang, Wenru -- Muller, Christa E -- Yang, Huaiyu -- Jiang, Hualiang -- Cherezov, Vadim -- Katritch, Vsevolod -- Jacobson, Kenneth A -- Stevens, Raymond C -- Wu, Beili -- Zhao, Qiang -- R01 AI100604/AI/NIAID NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- ZIA DK031126-07/Intramural NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):115-8. doi: 10.1038/nature13083. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China [2]. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670650" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Disulfides/metabolism ; Fibrinolytic Agents/*chemistry ; Humans ; Ligands ; Models, Molecular ; Molecular Docking Simulation ; Niacin/*analogs & derivatives/chemistry/metabolism ; Protein Conformation ; Purinergic P2Y Receptor Antagonists/chemistry/metabolism ; Receptors, Purinergic P2Y12/*chemistry/metabolism ; Sulfonamides/*chemistry/metabolism
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  • 47
    Publication Date: 2014-09-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scott, William G -- England -- Nature. 2014 Sep 4;513(7516):42-3. doi: 10.1038/513042a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry &Biochemistry and the Center for the Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, California 95064, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186897" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Color ; Crystallization ; *Fluorescence ; Fluorescent Dyes/analysis/chemistry ; Models, Molecular ; Molecular Imaging/*methods ; *Nucleotide Motifs ; RNA/*analysis/*chemistry/genetics/metabolism ; Staining and Labeling/*methods
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  • 48
    Publication Date: 2014-06-10
    Description: RNA is arguably the most functionally diverse biological macromolecule. In some cases a single discrete RNA sequence performs multiple roles, and this can be conferred by a complex three-dimensional structure. Such multifunctionality can also be driven or enhanced by the ability of a given RNA to assume different conformational (and therefore functional) states. Despite its biological importance, a detailed structural understanding of the paradigm of RNA structure-driven multifunctionality is lacking. To address this gap it is useful to study examples from single-stranded positive-sense RNA viruses, a prototype being the tRNA-like structure (TLS) found at the 3' end of the turnip yellow mosaic virus (TYMV). This TLS not only acts like a tRNA to drive aminoacylation of the viral genomic (g)RNA, but also interacts with other structures in the 3' untranslated region of the gRNA, contains the promoter for negative-strand synthesis, and influences several infection-critical processes. TLS RNA can provide a glimpse into the structural basis of RNA multifunctionality and plasticity, but for decades its high-resolution structure has remained elusive. Here we present the crystal structure of the complete TYMV TLS to 2.0 A resolution. Globally, the RNA adopts a shape that mimics tRNA, but it uses a very different set of intramolecular interactions to achieve this shape. These interactions also allow the TLS to readily switch conformations. In addition, the TLS structure is 'two faced': one face closely mimics tRNA and drives aminoacylation, the other face diverges from tRNA and enables additional functionality. The TLS is thus structured to perform several functions and interact with diverse binding partners, and we demonstrate its ability to specifically bind to ribosomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136544/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136544/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colussi, Timothy M -- Costantino, David A -- Hammond, John A -- Ruehle, Grant M -- Nix, Jay C -- Kieft, Jeffrey S -- GM081346/GM/NIGMS NIH HHS/ -- GM097333/GM/NIGMS NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P30CA046934/CA/NCI NIH HHS/ -- R01 GM081346/GM/NIGMS NIH HHS/ -- R01 GM097333/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 17;511(7509):366-9. doi: 10.1038/nature13378. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [3] Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA (T.M.C.); Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California 92037, USA (J.A.H.). ; 1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; 1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA (T.M.C.); Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California 92037, USA (J.A.H.). ; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909993" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Amino Acyl-tRNA Synthetases/metabolism ; Aminoacylation ; Base Sequence ; Crystallography, X-Ray ; Models, Molecular ; *Molecular Mimicry ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Protein Binding ; RNA Folding ; RNA, Guide/genetics/metabolism ; RNA, Transfer/*chemistry/genetics/metabolism ; RNA, Viral/*chemistry/genetics/*metabolism ; Ribosomes/chemistry/metabolism ; Tymovirus/*genetics
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  • 49
    Publication Date: 2014-05-13
    Description: Sulphur is an essential element for life and is ubiquitous in living systems. Yet how the sulphur atom is incorporated into many sulphur-containing secondary metabolites is poorly understood. For bond formation between carbon and sulphur in primary metabolites, the major ionic sulphur sources are the persulphide and thiocarboxylate groups on sulphur-carrier (donor) proteins. Each group is post-translationally generated through the action of a specific activating enzyme. In all reported bacterial cases, the gene encoding the enzyme that catalyses the carbon-sulphur bond formation reaction and that encoding the cognate sulphur-carrier protein exist in the same gene cluster. To study the production of the 2-thiosugar moiety in BE-7585A, an antibiotic from Amycolatopsis orientalis, we identified a putative 2-thioglucose synthase, BexX, whose protein sequence and mode of action seem similar to those of ThiG, the enzyme that catalyses thiazole formation in thiamine biosynthesis. However, no gene encoding a sulphur-carrier protein could be located in the BE-7585A cluster. Subsequent genome sequencing uncovered a few genes encoding sulphur-carrier proteins that are probably involved in the biosynthesis of primary metabolites but only one activating enzyme gene in the A. orientalis genome. Further experiments showed that this activating enzyme can adenylate each of these sulphur-carrier proteins and probably also catalyses the subsequent thiolation, through its rhodanese domain. A proper combination of these sulphur-delivery systems is effective for BexX-catalysed 2-thioglucose production. The ability of BexX to selectively distinguish sulphur-carrier proteins is given a structural basis using X-ray crystallography. This study is, to our knowledge, the first complete characterization of thiosugar formation in nature and also demonstrates the receptor promiscuity of the A. orientalis sulphur-delivery system. Our results also show that co-opting the sulphur-delivery machinery of primary metabolism for the biosynthesis of sulphur-containing natural products is probably a general strategy found in nature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Eita -- Zhang, Xuan -- Sun, He G -- Lu, Mei-yeh Jade -- Liu, Tsung-lin -- Ou, Albert -- Li, Jeng-yi -- Chen, Yu-hsiang -- Ealick, Steven E -- Liu, Hung-wen -- DK67081/DK/NIDDK NIH HHS/ -- GM035906/GM/NIGMS NIH HHS/ -- GM103403/GM/NIGMS NIH HHS/ -- GM103485/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41 GM103485/GM/NIGMS NIH HHS/ -- R01 DK067081/DK/NIDDK NIH HHS/ -- R01 GM035906/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):427-31. doi: 10.1038/nature13256. Epub 2014 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA. ; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA. ; Division of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, USA. ; 1] Biodiversity Research Center, Academia Sinica, Taipei 115, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei 115, Taiwan. ; 1] Genomics Research Center, Academia Sinica, Taipei 115, Taiwan [2] Institute of Bioinformatics and Biosignal Transduction, National Cheng-Kung University, Tainan 701, Taiwan. ; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan. ; Biodiversity Research Center, Academia Sinica, Taipei 115, Taiwan. ; 1] Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA [2] Division of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24814342" target="_blank"〉PubMed〈/a〉
    Keywords: Actinomycetales/*enzymology/*genetics/metabolism ; Carrier Proteins/chemistry/*metabolism ; Catalytic Domain ; Genome, Bacterial/genetics ; Ligases/*chemistry/genetics/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Tertiary ; Sulfur/*metabolism ; Thiosugars/*metabolism
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  • 50
    Publication Date: 2014-10-25
    Description: We present the high-quality genome sequence of a approximately 45,000-year-old modern human male from Siberia. This individual derives from a population that lived before-or simultaneously with-the separation of the populations in western and eastern Eurasia and carries a similar amount of Neanderthal ancestry as present-day Eurasians. However, the genomic segments of Neanderthal ancestry are substantially longer than those observed in present-day individuals, indicating that Neanderthal gene flow into the ancestors of this individual occurred 7,000-13,000 years before he lived. We estimate an autosomal mutation rate of 0.4 x 10(-9) to 0.6 x 10(-9) per site per year, a Y chromosomal mutation rate of 0.7 x 10(-9) to 0.9 x 10(-9) per site per year based on the additional substitutions that have occurred in present-day non-Africans compared to this genome, and a mitochondrial mutation rate of 1.8 x 10(-8) to 3.2 x 10(-8) per site per year based on the age of the bone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753769/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753769/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fu, Qiaomei -- Li, Heng -- Moorjani, Priya -- Jay, Flora -- Slepchenko, Sergey M -- Bondarev, Aleksei A -- Johnson, Philip L F -- Aximu-Petri, Ayinuer -- Prufer, Kay -- de Filippo, Cesare -- Meyer, Matthias -- Zwyns, Nicolas -- Salazar-Garcia, Domingo C -- Kuzmin, Yaroslav V -- Keates, Susan G -- Kosintsev, Pavel A -- Razhev, Dmitry I -- Richards, Michael P -- Peristov, Nikolai V -- Lachmann, Michael -- Douka, Katerina -- Higham, Thomas F G -- Slatkin, Montgomery -- Hublin, Jean-Jacques -- Reich, David -- Kelso, Janet -- Viola, T Bence -- Paabo, Svante -- F32 GM115006/GM/NIGMS NIH HHS/ -- GM100233/GM/NIGMS NIH HHS/ -- K99 GM104158/GM/NIGMS NIH HHS/ -- K99-GM104158/GM/NIGMS NIH HHS/ -- R01 GM100233/GM/NIGMS NIH HHS/ -- R01-GM40282/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 23;514(7523):445-9. doi: 10.1038/nature13810.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Key Laboratory of Vertebrate Evolution and Human Origins of Chinese Academy of Sciences, IVPP, CAS, Beijing 100044, China [2] Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Biological Sciences, Columbia University, New York, New York 10027, USA. ; Department of Integrative Biology, University of California, Berkeley, California 94720-3140, USA. ; Institute for Problems of the Development of the North, Siberian Branch of the Russian Academy of Sciences, Tyumen 625026, Russia. ; Expert Criminalistics Center, Omsk Division of the Ministry of Internal Affairs, Omsk 644007, Russia. ; Department of Biology, Emory University, Atlanta, Georgia 30322, USA. ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany. ; 1] Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany [2] Department of Anthropology, University of California, Davis, California 95616, USA. ; 1] Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany [2] Department of Archaeology, University of Cape Town, Cape Town 7701, South Africa [3] Departament de Prehistoria i Arqueologia, Universitat de Valencia, Valencia 46010, Spain [4] Research Group on Plant Foods in Hominin Dietary Ecology, Max-Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany. ; Institute of Geology and Mineralogy, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia. ; Institute of Plant and Animal Ecology, Urals Branch of the Russian Academy of Sciences, Yekaterinburg 620144, Russia. ; 1] Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany [2] Laboratory of Archaeology, Department of Anthropology, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada. ; Siberian Cultural Center, Omsk 644010, Russia. ; 1] Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany [2] Santa Fe Institute, Santa Fe, New Mexico 87501, USA. ; Oxford Radiocarbon Accelerator Unit, Research Laboratory for Archaeology and the History of Art, University of Oxford, Oxford OX1 3QY, UK. ; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany [2] Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25341783" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Chromosomes, Human, Pair 12/genetics ; Diet ; Evolution, Molecular ; *Fossils ; Genome, Human/*genetics ; Humans ; Hybridization, Genetic/genetics ; Male ; Molecular Sequence Data ; Mutation Rate ; Neanderthals/genetics ; Phylogeny ; Population Density ; Population Dynamics ; Principal Component Analysis ; Sequence Analysis, DNA ; Siberia
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  • 51
    Publication Date: 2014-07-06
    Description: A reduction in the number of digits has evolved many times in tetrapods, particularly in cursorial mammals that travel over deserts and plains, yet the underlying developmental mechanisms have remained elusive. Here we show that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the 'odd-toed' jerboa (Dipus sagitta) and horse and the 'even-toed' camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms including downregulation of Ptch1 expression but no increase in cell death. Together these data demonstrate remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphological convergence, particularly within the artiodactyl lineage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228958/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cooper, Kimberly L -- Sears, Karen E -- Uygur, Aysu -- Maier, Jennifer -- Baczkowski, Karl-Stephan -- Brosnahan, Margaret -- Antczak, Doug -- Skidmore, Julian A -- Tabin, Clifford J -- R37 HD032443/HD/NICHD NIH HHS/ -- R37HD032443/HD/NICHD NIH HHS/ -- England -- Nature. 2014 Jul 3;511(7507):41-5. doi: 10.1038/nature13496. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA. [3]. ; 1] Department of Animal Biology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA [2]. ; 1] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [2]. ; Department of Animal Biology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA. ; cole Normale Superieure de Lyon, 69007 Lyon, France. ; Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA. ; The Camel Reproduction Centre, Dubai, United Arab Emirates. ; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990742" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; *Body Patterning/genetics ; Camels/anatomy & histology/embryology ; Cell Death ; *Chondrogenesis/genetics ; Extremities/*anatomy & histology/*embryology ; Fibroblast Growth Factor 8/genetics ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/genetics ; Homeodomain Proteins/genetics ; Horses/anatomy & histology/embryology ; Mammals/*anatomy & histology/*embryology/genetics ; Mice ; Oncogene Proteins/genetics ; Phylogeny ; Receptors, Cell Surface/genetics ; Rodentia/anatomy & histology/embryology ; Swine/anatomy & histology/embryology ; Trans-Activators/genetics
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  • 52
    Publication Date: 2014-04-04
    Description: Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gad, Helge -- Koolmeister, Tobias -- Jemth, Ann-Sofie -- Eshtad, Saeed -- Jacques, Sylvain A -- Strom, Cecilia E -- Svensson, Linda M -- Schultz, Niklas -- Lundback, Thomas -- Einarsdottir, Berglind Osk -- Saleh, Aljona -- Gokturk, Camilla -- Baranczewski, Pawel -- Svensson, Richard -- Berntsson, Ronnie P-A -- Gustafsson, Robert -- Stromberg, Kia -- Sanjiv, Kumar -- Jacques-Cordonnier, Marie-Caroline -- Desroses, Matthieu -- Gustavsson, Anna-Lena -- Olofsson, Roger -- Johansson, Fredrik -- Homan, Evert J -- Loseva, Olga -- Brautigam, Lars -- Johansson, Lars -- Hoglund, Andreas -- Hagenkort, Anna -- Pham, Therese -- Altun, Mikael -- Gaugaz, Fabienne Z -- Vikingsson, Svante -- Evers, Bastiaan -- Henriksson, Martin -- Vallin, Karl S A -- Wallner, Olov A -- Hammarstrom, Lars G J -- Wiita, Elisee -- Almlof, Ingrid -- Kalderen, Christina -- Axelsson, Hanna -- Djureinovic, Tatjana -- Puigvert, Jordi Carreras -- Haggblad, Maria -- Jeppsson, Fredrik -- Martens, Ulf -- Lundin, Cecilia -- Lundgren, Bo -- Granelli, Ingrid -- Jensen, Annika Jenmalm -- Artursson, Per -- Nilsson, Jonas A -- Stenmark, Pal -- Scobie, Martin -- Berglund, Ulrika Warpman -- Helleday, Thomas -- England -- Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2]. ; Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden. ; Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; 1] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Clinical Pharmacology, Department of Medical and Health Sciences, Linkoping University, S-58185 Linkoping, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; 1] Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695224" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Cell Death/drug effects ; Cell Survival/drug effects ; Crystallization ; DNA Damage ; DNA Repair Enzymes/*antagonists & inhibitors/chemistry/metabolism ; Deoxyguanine Nucleotides/metabolism ; Enzyme Inhibitors/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Female ; Humans ; Male ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular Targeted Therapy ; Neoplasms/*drug therapy/*metabolism/pathology ; Nucleotides/*metabolism ; Oxidation-Reduction/drug effects ; Phosphoric Monoester Hydrolases/*antagonists & inhibitors/chemistry/metabolism ; Pyrimidines/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Pyrophosphatases/antagonists & inhibitors ; Reproducibility of Results ; Xenograft Model Antitumor Assays
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  • 53
    Publication Date: 2014-11-11
    Description: The move of vertebrates to a terrestrial lifestyle required major adaptations in their locomotory apparatus and reproductive organs. While the fin-to-limb transition has received considerable attention, little is known about the developmental and evolutionary origins of external genitalia. Similarities in gene expression have been interpreted as a potential evolutionary link between the limb and genitals; however, no underlying developmental mechanism has been identified. We re-examined this question using micro-computed tomography, lineage tracing in three amniote clades, and RNA-sequencing-based transcriptional profiling. Here we show that the developmental origin of external genitalia has shifted through evolution, and in some taxa limbs and genitals share a common primordium. In squamates, the genitalia develop directly from the budding hindlimbs, or the remnants thereof, whereas in mice the genital tubercle originates from the ventral and tail bud mesenchyme. The recruitment of different cell populations for genital outgrowth follows a change in the relative position of the cloaca, the genitalia organizing centre. Ectopic grafting of the cloaca demonstrates the conserved ability of different mesenchymal cells to respond to these genitalia-inducing signals. Our results support a limb-like developmental origin of external genitalia as the ancestral condition. Moreover, they suggest that a change in the relative position of the cloacal signalling centre during evolution has led to an altered developmental route for external genitalia in mammals, while preserving parts of the ancestral limb molecular circuitry owing to a common evolutionary origin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294627/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294627/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tschopp, Patrick -- Sherratt, Emma -- Sanger, Thomas J -- Groner, Anna C -- Aspiras, Ariel C -- Hu, Jimmy K -- Pourquie, Olivier -- Gros, Jerome -- Tabin, Clifford J -- R37 HD032443/HD/NICHD NIH HHS/ -- R37-HD032443/HD/NICHD NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):391-4. doi: 10.1038/nature13819. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; 1] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), 67400 Illkirch, France [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Developmental and Stem Cell Biology Department, Institut Pasteur, 75724 Paris Cedex 15, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383527" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Cell Lineage ; Cloaca/anatomy & histology/*embryology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genitalia/anatomy & histology/*embryology/metabolism ; Mice ; Phylogeny ; Signal Transduction ; Snakes/embryology ; Tissue Transplantation ; X-Ray Microtomography
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  • 54
    Publication Date: 2014-02-07
    Description: Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260937/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Correia, Bruno E -- Bates, John T -- Loomis, Rebecca J -- Baneyx, Gretchen -- Carrico, Chris -- Jardine, Joseph G -- Rupert, Peter -- Correnti, Colin -- Kalyuzhniy, Oleksandr -- Vittal, Vinayak -- Connell, Mary J -- Stevens, Eric -- Schroeter, Alexandria -- Chen, Man -- Macpherson, Skye -- Serra, Andreia M -- Adachi, Yumiko -- Holmes, Margaret A -- Li, Yuxing -- Klevit, Rachel E -- Graham, Barney S -- Wyatt, Richard T -- Baker, David -- Strong, Roland K -- Crowe, James E Jr -- Johnson, Philip R -- Schief, William R -- 1R01AI102766-01A1/AI/NIAID NIH HHS/ -- 1UM1AI100663/AI/NIAID NIH HHS/ -- 2T32GM007270/GM/NIGMS NIH HHS/ -- 5R21AI088554/AI/NIAID NIH HHS/ -- P01 AI094419/AI/NIAID NIH HHS/ -- P01AI094419/AI/NIAID NIH HHS/ -- P30 AI036214/AI/NIAID NIH HHS/ -- P30 AI045008/AI/NIAID NIH HHS/ -- P30AI36214/AI/NIAID NIH HHS/ -- R01 AI102766/AI/NIAID NIH HHS/ -- R21 AI088554/AI/NIAID NIH HHS/ -- T32 CA080416/CA/NCI NIH HHS/ -- T32 GM007270/GM/NIGMS NIH HHS/ -- T32CA080416/CA/NCI NIH HHS/ -- U54 AI 005714/AI/NIAID NIH HHS/ -- U54 AI057141/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):201-6. doi: 10.1038/nature12966. Epub 2014 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] PhD Program in Computational Biology, Instituto Gulbenkian Ciencia and Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal [3] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA [2]. ; 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA [3] Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499818" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Antibodies, Monoclonal/analysis/immunology ; Antibodies, Neutralizing/analysis/immunology ; Antibodies, Viral/analysis/immunology ; Antigens, Viral/chemistry/immunology ; Crystallography, X-Ray ; *Drug Design ; Enzyme-Linked Immunosorbent Assay ; Epitopes/*chemistry/*immunology ; Macaca mulatta/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Neutralization Tests ; Protein Conformation ; *Protein Stability ; Respiratory Syncytial Virus Vaccines/*chemistry/*immunology ; Respiratory Syncytial Viruses/chemistry/immunology
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  • 55
    Publication Date: 2014-12-04
    Description: Photosynthesis converts light energy into biologically useful chemical energy vital to life on Earth. The initial reaction of photosynthesis takes place in photosystem II (PSII), a 700-kilodalton homodimeric membrane protein complex that catalyses photo-oxidation of water into dioxygen through an S-state cycle of the oxygen evolving complex (OEC). The structure of PSII has been solved by X-ray diffraction (XRD) at 1.9 angstrom resolution, which revealed that the OEC is a Mn4CaO5-cluster coordinated by a well defined protein environment. However, extended X-ray absorption fine structure (EXAFS) studies showed that the manganese cations in the OEC are easily reduced by X-ray irradiation, and slight differences were found in the Mn-Mn distances determined by XRD, EXAFS and theoretical studies. Here we report a 'radiation-damage-free' structure of PSII from Thermosynechococcus vulcanus in the S1 state at a resolution of 1.95 angstroms using femtosecond X-ray pulses of the SPring-8 angstrom compact free-electron laser (SACLA) and hundreds of large, highly isomorphous PSII crystals. Compared with the structure from XRD, the OEC in the X-ray free electron laser structure has Mn-Mn distances that are shorter by 0.1-0.2 angstroms. The valences of each manganese atom were tentatively assigned as Mn1D(III), Mn2C(IV), Mn3B(IV) and Mn4A(III), based on the average Mn-ligand distances and analysis of the Jahn-Teller axis on Mn(III). One of the oxo-bridged oxygens, O5, has significantly longer distances to Mn than do the other oxo-oxygen atoms, suggesting that O5 is a hydroxide ion instead of a normal oxygen dianion and therefore may serve as one of the substrate oxygen atoms. These findings provide a structural basis for the mechanism of oxygen evolution, and we expect that this structure will provide a blueprint for the design of artificial catalysts for water oxidation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suga, Michihiro -- Akita, Fusamichi -- Hirata, Kunio -- Ueno, Go -- Murakami, Hironori -- Nakajima, Yoshiki -- Shimizu, Tetsuya -- Yamashita, Keitaro -- Yamamoto, Masaki -- Ago, Hideo -- Shen, Jian-Ren -- England -- Nature. 2015 Jan 1;517(7532):99-103. doi: 10.1038/nature13991. Epub 2014 Nov 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Photosynthesis Research Center, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima Naka, Okayama 700-8530, Japan. ; 1] RIKEN SPring-8 Center, 1-1-1 Kouto Sayo, Hyogo 679-5148, Japan [2] Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Saitama 332-0012, Japan. ; RIKEN SPring-8 Center, 1-1-1 Kouto Sayo, Hyogo 679-5148, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470056" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallization ; Cyanobacteria/*enzymology ; Electrons ; Lasers ; Manganese/chemistry ; Models, Molecular ; Oxygen/chemistry/metabolism ; Photosystem II Protein Complex/*chemistry/*radiation effects ; Synchrotrons ; Time Factors ; Water/chemistry/metabolism ; *X-Rays
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  • 56
    Publication Date: 2014-01-28
    Description: What mechanisms underlie the transitions responsible for the diverse shapes observed in the living world? Although bacteria exhibit a myriad of morphologies, the mechanisms responsible for the evolution of bacterial cell shape are not understood. We investigated morphological diversity in a group of bacteria that synthesize an appendage-like extension of the cell envelope called the stalk. The location and number of stalks varies among species, as exemplified by three distinct subcellular positions of stalks within a rod-shaped cell body: polar in the genus Caulobacter and subpolar or bilateral in the genus Asticcacaulis. Here we show that a developmental regulator of Caulobacter crescentus, SpmX, is co-opted in the genus Asticcacaulis to specify stalk synthesis either at the subpolar or bilateral positions. We also show that stepwise evolution of a specific region of SpmX led to the gain of a new function and localization of this protein, which drove the sequential transition in stalk positioning. Our results indicate that changes in protein function, co-option and modularity are key elements in the evolution of bacterial morphology. Therefore, similar evolutionary principles of morphological transitions apply to both single-celled prokaryotes and multicellular eukaryotes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Chao -- Brown, Pamela J B -- Ducret, Adrien -- Brun, Yves V -- AI072992/AI/NIAID NIH HHS/ -- GM051986/GM/NIGMS NIH HHS/ -- R01 GM051986/GM/NIGMS NIH HHS/ -- S10RR028697-01/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):489-93. doi: 10.1038/nature12900. Epub 2014 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Indiana University, Bloomington, Indiana 47405, USA. ; 1] Department of Biology, Indiana University, Bloomington, Indiana 47405, USA [2] Division of Biological Sciences, University of Missouri, Columbia, Missouri 65211, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463524" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*cytology/*metabolism ; Bacterial Proteins/*metabolism ; *Biological Evolution ; Caulobacter crescentus/cytology/metabolism ; Caulobacteraceae/cytology/metabolism ; Cell Membrane/metabolism ; *Cell Polarity ; Evolution, Molecular ; Models, Biological ; Molecular Sequence Data ; Phylogeny ; Protein Transport
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  • 57
    Publication Date: 2014-09-12
    Description: The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garreau de Loubresse, Nicolas -- Prokhorova, Irina -- Holtkamp, Wolf -- Rodnina, Marina V -- Yusupova, Gulnara -- Yusupov, Marat -- 294312/European Research Council/International -- England -- Nature. 2014 Sep 25;513(7519):517-22. doi: 10.1038/nature13737. Epub 2014 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Universite de Strasbourg, 67404, Illkirch, France. ; Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209664" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites/drug effects ; Crystallography, X-Ray ; Cycloheximide/pharmacology ; Drug Resistance/drug effects ; Eukaryotic Cells/*chemistry/drug effects/enzymology ; Kinetics ; Macrolides/pharmacology ; Models, Molecular ; Molecular Targeted Therapy ; Molecular Weight ; Peptide Chain Elongation, Translational/drug effects ; Peptidyl Transferases/chemistry/metabolism ; Piperidones/pharmacology ; Protein Synthesis Inhibitors/*chemistry/*pharmacology ; RNA, Messenger/genetics/metabolism ; RNA, Transfer/genetics/metabolism ; Ribosome Subunits, Large, Eukaryotic/chemistry/drug effects/metabolism ; Ribosomes/*chemistry/*drug effects/metabolism ; Saccharomyces cerevisiae/*chemistry ; Species Specificity ; Substrate Specificity
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  • 58
    Publication Date: 2014-10-16
    Description: The mechanisms that underlie the origin of major prokaryotic groups are poorly understood. In principle, the origin of both species and higher taxa among prokaryotes should entail similar mechanisms--ecological interactions with the environment paired with natural genetic variation involving lineage-specific gene innovations and lineage-specific gene acquisitions. To investigate the origin of higher taxa in archaea, we have determined gene distributions and gene phylogenies for the 267,568 protein-coding genes of 134 sequenced archaeal genomes in the context of their homologues from 1,847 reference bacterial genomes. Archaeal-specific gene families define 13 traditionally recognized archaeal higher taxa in our sample. Here we report that the origins of these 13 groups unexpectedly correspond to 2,264 group-specific gene acquisitions from bacteria. Interdomain gene transfer is highly asymmetric, transfers from bacteria to archaea are more than fivefold more frequent than vice versa. Gene transfers identified at major evolutionary transitions among prokaryotes specifically implicate gene acquisitions for metabolic functions from bacteria as key innovations in the origin of higher archaeal taxa.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285555/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285555/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nelson-Sathi, Shijulal -- Sousa, Filipa L -- Roettger, Mayo -- Lozada-Chavez, Nabor -- Thiergart, Thorsten -- Janssen, Arnold -- Bryant, David -- Landan, Giddy -- Schonheit, Peter -- Siebers, Bettina -- McInerney, James O -- Martin, William F -- 232975/European Research Council/International -- England -- Nature. 2015 Jan 1;517(7532):77-80. doi: 10.1038/nature13805. Epub 2014 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Evolution, Heinrich-Heine University, 40225 Dusseldorf, Germany. ; Mathematisches Institut, Heinrich-Heine University, 40225 Dusseldorf, Germany. ; Department of Mathematics and Statistics, University of Otago, Dunedin 9054, New Zealand. ; Genomic Microbiology Group, Institute of Microbiology, Christian-Albrechts-Universitat Kiel, 24118 Kiel, Germany. ; Institut fur Allgemeine Mikrobiologie, Christian-Albrechts-Universitat Kiel, 24118 Kiel, Germany. ; Faculty of Chemistry, Biofilm Centre, Molecular Enzyme Technology and Biochemistry, University of Duisburg-Essen, 45117 Essen, Germany. ; Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland. ; 1] Institute of Molecular Evolution, Heinrich-Heine University, 40225 Dusseldorf, Germany [2] Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25317564" target="_blank"〉PubMed〈/a〉
    Keywords: Archaea/*classification/*genetics/metabolism ; Archaeal Proteins/genetics ; Bacteria/*genetics/metabolism ; *Evolution, Molecular ; Gene Transfer, Horizontal/*genetics ; Genes, Archaeal/*genetics ; Genes, Bacterial/*genetics ; Genome, Archaeal/genetics ; Phylogeny
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  • 59
    Publication Date: 2014-11-20
    Description: Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine. Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol beta, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312183/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312183/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Freudenthal, Bret D -- Beard, William A -- Perera, Lalith -- Shock, David D -- Kim, Taejin -- Schlick, Tamar -- Wilson, Samuel H -- 1U19CA105010/CA/NCI NIH HHS/ -- U19 CA177547/CA/NCI NIH HHS/ -- Z01-ES050158/ES/NIEHS NIH HHS/ -- Z01-ES050161/ES/NIEHS NIH HHS/ -- ZIA ES050158-18/Intramural NIH HHS/ -- ZIA ES050159-18/Intramural NIH HHS/ -- ZIC-ES043010/ES/NIEHS NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):635-9. doi: 10.1038/nature13886. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, North Carolina 27709-2233, USA. ; 1] Department of Chemistry, New York University, and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, 10th Floor Silver Center, 100 Washington Square East, New York, New York 10003, USA [2] Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, New York 10012, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409153" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/chemistry/metabolism ; Base Pairing ; Catalytic Domain ; Crystallography, X-Ray ; Cytosine/chemistry/metabolism ; Cytotoxins/chemistry/*metabolism/toxicity ; DNA/biosynthesis/chemistry ; *DNA Damage ; DNA Polymerase beta/*chemistry/*metabolism ; DNA Repair ; DNA Replication ; Deoxyguanine Nucleotides/chemistry/*metabolism/*toxicity ; Guanine/analogs & derivatives/chemistry/metabolism ; Humans ; Hydrogen Bonding ; Kinetics ; Models, Molecular ; Molecular Conformation ; *Mutagenesis ; Neoplasms/enzymology/genetics ; Oxidation-Reduction ; Oxidative Stress ; Static Electricity ; Substrate Specificity ; Time Factors
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  • 60
    Publication Date: 2014-02-07
    Description: The biogenesis of secretory as well as transmembrane proteins requires the activity of the universally conserved protein-conducting channel (PCC), the Sec61 complex (SecY complex in bacteria). In eukaryotic cells the PCC is located in the membrane of the endoplasmic reticulum where it can bind to translating ribosomes for co-translational protein transport. The Sec complex consists of three subunits (Sec61alpha, beta and gamma) and provides an aqueous environment for the translocation of hydrophilic peptides as well as a lateral opening in the Sec61alpha subunit that has been proposed to act as a gate for the membrane partitioning of hydrophobic domains. A plug helix and a so-called pore ring are believed to seal the PCC against ion flow and are proposed to rearrange for accommodation of translocating peptides. Several crystal and cryo-electron microscopy structures revealed different conformations of closed and partially open Sec61 and SecY complexes. However, in none of these samples has the translocation state been unambiguously defined biochemically. Here we present cryo-electron microscopy structures of ribosome-bound Sec61 complexes engaged in translocation or membrane insertion of nascent peptides. Our data show that a hydrophilic peptide can translocate through the Sec complex with an essentially closed lateral gate and an only slightly rearranged central channel. Membrane insertion of a hydrophobic domain seems to occur with the Sec complex opening the proposed lateral gate while rearranging the plug to maintain an ion permeability barrier. Taken together, we provide a structural model for the basic activities of the Sec61 complex as a protein-conducting channel.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gogala, Marko -- Becker, Thomas -- Beatrix, Birgitta -- Armache, Jean-Paul -- Barrio-Garcia, Clara -- Berninghausen, Otto -- Beckmann, Roland -- England -- Nature. 2014 Feb 6;506(7486):107-10. doi: 10.1038/nature12950.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Center for integrated Protein Science Munich, Department of Biochemistry, Feodor-Lynen-Strasse 25, University of Munich, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499919" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/*metabolism/ultrastructure ; Cryoelectron Microscopy ; Dogs ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins/chemistry/*metabolism/*ultrastructure ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism/*ultrastructure ; Peptides/chemistry/*metabolism ; *Protein Biosynthesis ; Protein Subunits/*chemistry/metabolism ; Protein Transport ; Ribosomes/chemistry/*metabolism/ultrastructure
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  • 61
    Publication Date: 2014-04-18
    Description: The evolution of serially arranged, jointed endoskeletal supports internal to the gills--the visceral branchial arches--represents one of the key events in early jawed vertebrate (gnathostome) history, because it provided the morphological basis for the subsequent evolution of jaws. However, until now little was known about visceral arches in early gnathostomes, and theories about gill arch evolution were driven by information gleaned mostly from both modern cartilaginous (chondrichthyan) and bony (osteichthyan) fishes. New fossil discoveries can profoundly affect our understanding of evolutionary history, by revealing hitherto unseen combinations of primitive and derived characters. Here we describe a 325 million year (Myr)-old Palaeozoic shark-like fossil that represents, to our knowledge, the earliest identified chondrichthyan in which the complete gill skeleton is three-dimensionally preserved in its natural position. Its visceral arch arrangement is remarkably osteichthyan-like, suggesting that this may represent the common ancestral condition for crown gnathostomes. Our findings thus reinterpret the polarity of some arch features of the crown jawed vertebrates and invert the classic hypothesis, in which modern sharks retain the ancestral condition. This study underscores the importance of early chondrichthyans in resolving the evolutionary history of jawed vertebrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pradel, Alan -- Maisey, John G -- Tafforeau, Paul -- Mapes, Royal H -- Mallatt, Jon -- England -- Nature. 2014 May 29;509(7502):608-11. doi: 10.1038/nature13195. Epub 2014 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Vertebrate Paleontology, American Museum of Natural History, Central Park West at 79th Street, New York, New York 10024, USA. ; European Synchrotron Radiation Facility, BP 220, 6 rue Jules Horowitz, 38043 Grenoble Cedex, France. ; Department of Geological Sciences, Ohio University, Athens, Ohio 45701, USA. ; School of Biological Sciences, Washington State University, Pullman, Washington 99164-4236, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739974" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Branchial Region/anatomy & histology ; Cartilage/anatomy & histology ; *Fossils ; Gills/*anatomy & histology ; Phylogeny ; Sharks/*anatomy & histology/classification
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  • 62
    Publication Date: 2014-11-11
    Description: The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca(2+)-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca(2+)-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca(2+)-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca(2+) coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl(-) channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca(2+) activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brunner, Janine D -- Lim, Novandy K -- Schenck, Stephan -- Duerst, Alessia -- Dutzler, Raimund -- England -- Nature. 2014 Dec 11;516(7530):207-12. doi: 10.1038/nature13984. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383531" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites/genetics ; Calcium/chemistry/*metabolism/pharmacology ; Chloride Channels/*chemistry/genetics/*metabolism ; Crystallography, X-Ray ; Electric Conductivity ; Humans ; Hydrophobic and Hydrophilic Interactions ; Ion Transport/drug effects ; Lipid Bilayers/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nectria/*chemistry/enzymology/genetics ; Neoplasm Proteins/chemistry ; Phospholipid Transfer Proteins/*chemistry/genetics/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Subunits/chemistry/metabolism
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  • 63
    Publication Date: 2014-04-30
    Description: Speciation generally involves a three-step process--range expansion, range fragmentation and the development of reproductive isolation between spatially separated populations. Speciation relies on cycling through these three steps and each may limit the rate at which new species form. We estimate phylogenetic relationships among all Himalayan songbirds to ask whether the development of reproductive isolation and ecological competition, both factors that limit range expansions, set an ultimate limit on speciation. Based on a phylogeny for all 358 species distributed along the eastern elevational gradient, here we show that body size and shape differences evolved early in the radiation, with the elevational band occupied by a species evolving later. These results are consistent with competition for niche space limiting species accumulation. Even the elevation dimension seems to be approaching ecological saturation, because the closest relatives both inside the assemblage and elsewhere in the Himalayas are on average separated by more than five million years, which is longer than it generally takes for reproductive isolation to be completed; also, elevational distributions are well explained by resource availability, notably the abundance of arthropods, and not by differences in diversification rates in different elevational zones. Our results imply that speciation rate is ultimately set by niche filling (that is, ecological competition for resources), rather than by the rate of acquisition of reproductive isolation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Price, Trevor D -- Hooper, Daniel M -- Buchanan, Caitlyn D -- Johansson, Ulf S -- Tietze, D Thomas -- Alstrom, Per -- Olsson, Urban -- Ghosh-Harihar, Mousumi -- Ishtiaq, Farah -- Gupta, Sandeep K -- Martens, Jochen -- Harr, Bettina -- Singh, Pratap -- Mohan, Dhananjai -- England -- Nature. 2014 May 8;509(7499):222-5. doi: 10.1038/nature13272. Epub 2014 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA. ; 1] Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA [2] Department of Zoology, Swedish Museum of Natural History, 10405 Stockholm, Sweden. ; 1] Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA [2] Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany. ; 1] Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China [2] Swedish Species Information Centre, Swedish University of Agricultural Sciences, Box 7007, 75007 Uppsala, Sweden. ; Systematics and Biodiversity, Department of Biology and Environmental Sciences, University of Gothenburg, 40530 Gothenburg, Sweden. ; Wildlife Institute of India, PO Box 18, Chandrabani, Dehradun 248001, India. ; Institute of Zoology, Johannes Gutenberg University, Mainz 55099, Germany. ; Max Planck Institute for Evolutionary Biology, August Thienemannstrasse 2, 24306 Plon, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776798" target="_blank"〉PubMed〈/a〉
    Keywords: *Altitude ; Animals ; Body Size ; China ; *Ecosystem ; *Genetic Speciation ; India ; Phylogeny ; Reproduction ; Songbirds/anatomy & histology/*classification/*physiology ; Tibet
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  • 64
    Publication Date: 2014-05-09
    Description: Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks to avoid stalling of the replication machinery and consequent genomic instability. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase alpha (Pol alpha) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a beta-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol alpha and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol alpha and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol alpha and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol alpha to one CMG helicase within the replisome, providing a new model for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of Escherichia coli. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simon, Aline C -- Zhou, Jin C -- Perera, Rajika L -- van Deursen, Frederick -- Evrin, Cecile -- Ivanova, Marina E -- Kilkenny, Mairi L -- Renault, Ludovic -- Kjaer, Svend -- Matak-Vinkovic, Dijana -- Labib, Karim -- Costa, Alessandro -- Pellegrini, Luca -- 084279/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):293-7. doi: 10.1038/nature13234. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2]. ; 1] Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK [2]. ; 1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2] Imperial College, South Kensington, London SW7 2AZ, UK (R.L.P.); Cancer Research UK London Research Institute, London WC2A 3LY, UK (M.E.I.). ; Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK. ; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK. ; Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK. ; Protein purification, Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805245" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DNA Helicases/chemistry/*metabolism/ultrastructure ; DNA Polymerase I/chemistry/*metabolism/ultrastructure ; *DNA Replication ; DNA-Binding Proteins/*chemistry/*metabolism/ultrastructure ; DNA-Directed DNA Polymerase/*chemistry/*metabolism ; Microscopy, Electron ; Minichromosome Maintenance Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multienzyme Complexes/*chemistry/*metabolism ; Nuclear Proteins/chemistry/metabolism ; Protein Binding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Saccharomyces cerevisiae/*chemistry/ultrastructure ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism/ultrastructure
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 65
    Publication Date: 2014-03-05
    Description: Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Hong -- Li, Yuanyuan -- Xi, Yuanxin -- Jiang, Shiming -- Stratton, Sabrina -- Peng, Danni -- Tanaka, Kaori -- Ren, Yongfeng -- Xia, Zheng -- Wu, Jun -- Li, Bing -- Barton, Michelle C -- Li, Wei -- Li, Haitao -- Shi, Xiaobing -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 GM090077/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01GM090077/GM/NIGMS NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):263-8. doi: 10.1038/nature13045. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Teaxs 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590075" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Carrier Proteins/chemistry/*metabolism ; Chromatin/genetics/metabolism ; Co-Repressor Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Histones/chemistry/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Oncogenes/genetics ; Prognosis ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase II/*metabolism ; Substrate Specificity ; *Transcription Elongation, Genetic
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  • 66
    Publication Date: 2014-10-02
    Description: Mitochondrial ribosomes (mitoribosomes) are extensively modified ribosomes of bacterial descent specialized for the synthesis and insertion of membrane proteins that are critical for energy conversion and ATP production inside mitochondria. Mammalian mitoribosomes, which comprise 39S and 28S subunits, have diverged markedly from the bacterial ribosomes from which they are derived, rendering them unique compared to bacterial, eukaryotic cytosolic and fungal mitochondrial ribosomes. We have previously determined at 4.9 A resolution the architecture of the porcine (Sus scrofa) 39S subunit, which is highly homologous to the human mitoribosomal large subunit. Here we present the complete atomic structure of the porcine 39S large mitoribosomal subunit determined in the context of a stalled translating mitoribosome at 3.4 A resolution by cryo-electron microscopy and chemical crosslinking/mass spectrometry. The structure reveals the locations and the detailed folds of 50 mitoribosomal proteins, shows the highly conserved mitoribosomal peptidyl transferase active site in complex with its substrate transfer RNAs, and defines the path of the nascent chain in mammalian mitoribosomes along their idiosyncratic exit tunnel. Furthermore, we present evidence that a mitochondrial tRNA has become an integral component of the central protuberance of the 39S subunit where it architecturally substitutes for the absence of the 5S ribosomal RNA, a ubiquitous component of all cytoplasmic ribosomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greber, Basil J -- Boehringer, Daniel -- Leibundgut, Marc -- Bieri, Philipp -- Leitner, Alexander -- Schmitz, Nikolaus -- Aebersold, Ruedi -- Ban, Nenad -- England -- Nature. 2014 Nov 13;515(7526):283-6. doi: 10.1038/nature13895. Epub 2014 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Biology, Institute of Molecular Systems Biology, Auguste-Piccard-Hof 1, ETH Zurich, CH-8093 Zurich, Switzerland. ; 1] Department of Biology, Institute of Molecular Systems Biology, Auguste-Piccard-Hof 1, ETH Zurich, CH-8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, CH-8057 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25271403" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cross-Linking Reagents ; Cryoelectron Microscopy ; Mass Spectrometry ; Mitochondria/*chemistry/ultrastructure ; Mitochondrial Proteins/*chemistry/metabolism/*ultrastructure ; Models, Molecular ; Molecular Conformation ; Peptidyl Transferases/metabolism ; RNA, Ribosomal/chemistry/metabolism/ultrastructure ; Ribosome Subunits, Large/*chemistry/genetics/*ultrastructure ; Sus scrofa/genetics
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  • 67
    Publication Date: 2014-07-06
    Description: Lipopolysaccharide (LPS) is essential for most Gram-negative bacteria and has crucial roles in protection of the bacteria from harsh environments and toxic compounds, including antibiotics. Seven LPS transport proteins (that is, LptA-LptG) form a trans-envelope protein complex responsible for the transport of LPS from the inner membrane to the outer membrane, the mechanism for which is poorly understood. Here we report the first crystal structure of the unique integral membrane LPS translocon LptD-LptE complex. LptD forms a novel 26-stranded beta-barrel, which is to our knowledge the largest beta-barrel reported so far. LptE adopts a roll-like structure located inside the barrel of LptD to form an unprecedented two-protein 'barrel and plug' architecture. The structure, molecular dynamics simulations and functional assays suggest that the hydrophilic O-antigen and the core oligosaccharide of the LPS may pass through the barrel and the lipid A of the LPS may be inserted into the outer leaflet of the outer membrane through a lateral opening between strands beta1 and beta26 of LptD. These findings not only help us to understand important aspects of bacterial outer membrane biogenesis, but also have significant potential for the development of novel drugs against multi-drug resistant pathogenic bacteria.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Haohao -- Xiang, Quanju -- Gu, Yinghong -- Wang, Zhongshan -- Paterson, Neil G -- Stansfeld, Phillip J -- He, Chuan -- Zhang, Yizheng -- Wang, Wenjian -- Dong, Changjiang -- 083501/Z/07/Z/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jul 3;511(7507):52-6. doi: 10.1038/nature13464. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK [2] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK. ; 1] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK [2] Department of Microbiology, College of Resource and Environment Science, Sichuan Agriculture University, Yaan 625000, China. ; Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. ; 1] Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK [2] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK [3] College of Life Sciences, Sichuan University, Chengdu 610065, China. ; Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK. ; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. ; 1] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK [2] School of Electronics and Information, Wuhan Technical College of Communications, No.6 Huangjiahu West Road, Hongshan District, Wuhan, Hubei 430065, China. ; College of Life Sciences, Sichuan University, Chengdu 610065, China. ; Laboratory of Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990744" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/*metabolism ; Cell Membrane/chemistry/metabolism ; Cell Wall/chemistry/metabolism ; Crystallography, X-Ray ; Lipopolysaccharides/chemistry/*metabolism ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism ; Protein Binding ; Protein Structure, Secondary ; Salmonella typhimurium/*chemistry/cytology ; Structure-Activity Relationship
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  • 68
    Publication Date: 2014-06-27
    Description: The polyketide synthase (PKS) mega-enzyme assembly line uses a modular architecture to synthesize diverse and bioactive natural products that often constitute the core structures or complete chemical entities for many clinically approved therapeutic agents. The architecture of a full-length PKS module from the pikromycin pathway of Streptomyces venezuelae creates a reaction chamber for the intramodule acyl carrier protein (ACP) domain that carries building blocks and intermediates between acyltransferase, ketosynthase and ketoreductase active sites (see accompanying paper). Here we determine electron cryo-microscopy structures of a full-length pikromycin PKS module in three key biochemical states of its catalytic cycle. Each biochemical state was confirmed by bottom-up liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry. The ACP domain is differentially and precisely positioned after polyketide chain substrate loading on the active site of the ketosynthase, after extension to the beta-keto intermediate, and after beta-hydroxy product generation. The structures reveal the ACP dynamics for sequential interactions with catalytic domains within the reaction chamber, and for transferring the elongated and processed polyketide substrate to the next module in the PKS pathway. During the enzymatic cycle the ketoreductase domain undergoes dramatic conformational rearrangements that enable optimal positioning for reductive processing of the ACP-bound polyketide chain elongation intermediate. These findings have crucial implications for the design of functional PKS modules, and for the engineering of pathways to generate pharmacologically relevant molecules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074775/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074775/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whicher, Jonathan R -- Dutta, Somnath -- Hansen, Douglas A -- Hale, Wendi A -- Chemler, Joseph A -- Dosey, Annie M -- Narayan, Alison R H -- Hakansson, Kristina -- Sherman, David H -- Smith, Janet L -- Skiniotis, Georgios -- 1R21CA138331-01A1/CA/NCI NIH HHS/ -- DK042303/DK/NIDDK NIH HHS/ -- DK090165/DK/NIDDK NIH HHS/ -- GM076477/GM/NIGMS NIH HHS/ -- R01 DK042303/DK/NIDDK NIH HHS/ -- R01 DK090165/DK/NIDDK NIH HHS/ -- R01 GM076477/GM/NIGMS NIH HHS/ -- T32 GM008597/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):560-4. doi: 10.1038/nature13409. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Chemical Biology Graduate Program, University of Michigan, Ann Arbor, Michigan 48109, USA [3]. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2]. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [4] Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24965656" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Carrier Protein/chemistry/metabolism/ultrastructure ; Acyltransferases/chemistry/metabolism/ultrastructure ; Alcohol Oxidoreductases/chemistry/metabolism/ultrastructure ; Bacterial Proteins/chemistry/metabolism/ultrastructure ; *Biocatalysis ; Catalytic Domain ; Cryoelectron Microscopy ; Macrolides/metabolism ; Models, Molecular ; Polyketide Synthases/*chemistry/*metabolism/ultrastructure ; Protein Structure, Tertiary ; Streptomyces/*enzymology
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  • 69
    Publication Date: 2014-09-05
    Description: Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353498/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353498/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brawand, David -- Wagner, Catherine E -- Li, Yang I -- Malinsky, Milan -- Keller, Irene -- Fan, Shaohua -- Simakov, Oleg -- Ng, Alvin Y -- Lim, Zhi Wei -- Bezault, Etienne -- Turner-Maier, Jason -- Johnson, Jeremy -- Alcazar, Rosa -- Noh, Hyun Ji -- Russell, Pamela -- Aken, Bronwen -- Alfoldi, Jessica -- Amemiya, Chris -- Azzouzi, Naoual -- Baroiller, Jean-Francois -- Barloy-Hubler, Frederique -- Berlin, Aaron -- Bloomquist, Ryan -- Carleton, Karen L -- Conte, Matthew A -- D'Cotta, Helena -- Eshel, Orly -- Gaffney, Leslie -- Galibert, Francis -- Gante, Hugo F -- Gnerre, Sante -- Greuter, Lucie -- Guyon, Richard -- Haddad, Natalie S -- Haerty, Wilfried -- Harris, Rayna M -- Hofmann, Hans A -- Hourlier, Thibaut -- Hulata, Gideon -- Jaffe, David B -- Lara, Marcia -- Lee, Alison P -- MacCallum, Iain -- Mwaiko, Salome -- Nikaido, Masato -- Nishihara, Hidenori -- Ozouf-Costaz, Catherine -- Penman, David J -- Przybylski, Dariusz -- Rakotomanga, Michaelle -- Renn, Suzy C P -- Ribeiro, Filipe J -- Ron, Micha -- Salzburger, Walter -- Sanchez-Pulido, Luis -- Santos, M Emilia -- Searle, Steve -- Sharpe, Ted -- Swofford, Ross -- Tan, Frederick J -- Williams, Louise -- Young, Sarah -- Yin, Shuangye -- Okada, Norihiro -- Kocher, Thomas D -- Miska, Eric A -- Lander, Eric S -- Venkatesh, Byrappa -- Fernald, Russell D -- Meyer, Axel -- Ponting, Chris P -- Streelman, J Todd -- Lindblad-Toh, Kerstin -- Seehausen, Ole -- Di Palma, Federica -- 2R01DE019637-04/DE/NIDCR NIH HHS/ -- F30 DE023013/DE/NIDCR NIH HHS/ -- MC_U137761446/Medical Research Council/United Kingdom -- R01 DE019637/DE/NIDCR NIH HHS/ -- R01 NS034950/NS/NINDS NIH HHS/ -- U54 HG002045/HG/NHGRI NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Sep 18;513(7518):375-81. doi: 10.1038/nature13726. Epub 2014 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, UK [3]. ; 1] Department of Fish Ecology and Evolution, Eawag Swiss Federal Institute of Aquatic Science and Technology, Center for Ecology, Evolution &Biogeochemistry, CH-6047 Kastanienbaum, Switzerland [2] Division of Aquatic Ecology, Institute of Ecology &Evolution, University of Bern, CH-3012 Bern, Switzerland [3]. ; 1] MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, UK [2]. ; 1] Gurdon Institute, Cambridge CB2 1QN, UK [2] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; Division of Aquatic Ecology, Institute of Ecology &Evolution, University of Bern, CH-3012 Bern, Switzerland. ; Department of Biology, University of Konstanz, D-78457 Konstanz, Germany. ; 1] Department of Biology, University of Konstanz, D-78457 Konstanz, Germany [2] European Molecular Biology Laboratory, 69117 Heidelberg, Germany. ; Institute of Molecular and Cell Biology, A*STAR, 138673 Singapore. ; Department of Biology, Reed College, Portland, Oregon 97202, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Biology Department, Stanford University, Stanford, California 94305-5020, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA. ; Institut Genetique et Developpement, CNRS/University of Rennes, 35043 Rennes, France. ; CIRAD, Campus International de Baillarguet, TA B-110/A, 34398 Montpellier cedex 5, France. ; School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, USA. ; Department of Biology, University of Maryland, College Park, Maryland 20742, USA. ; Animal Genetics, Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, 50250 Israel. ; Zoological Institute, University of Basel, CH-4051 Basel, Switzerland. ; 1] Department of Fish Ecology and Evolution, Eawag Swiss Federal Institute of Aquatic Science and Technology, Center for Ecology, Evolution &Biogeochemistry, CH-6047 Kastanienbaum, Switzerland [2] Division of Aquatic Ecology, Institute of Ecology &Evolution, University of Bern, CH-3012 Bern, Switzerland. ; MRC Functional Genomics Unit, University of Oxford, Oxford OX1 3QX, UK. ; Department of Integrative Biology, Center for Computational Biology and Bioinformatics; The University of Texas at Austin, Austin, Texas 78712, USA. ; Department of Fish Ecology and Evolution, Eawag Swiss Federal Institute of Aquatic Science and Technology, Center for Ecology, Evolution &Biogeochemistry, CH-6047 Kastanienbaum, Switzerland. ; Department of Biological Sciences, Tokyo Institute of Technology, Tokyo, 226-8501 Yokohama, Japan. ; Systematique, Adaptation, Evolution, National Museum of Natural History, 75005 Paris, France. ; Institute of Aquaculture, University of Stirling, Stirling FK9 4LA, UK. ; Carnegie Institution of Washington, Department of Embryology, 3520 San Martin Drive Baltimore, Maryland 21218, USA. ; 1] Department of Biological Sciences, Tokyo Institute of Technology, Tokyo, 226-8501 Yokohama, Japan [2] National Cheng Kung University, Tainan City, 704 Taiwan. ; Gurdon Institute, Cambridge CB2 1QN, UK. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Vertebrate and Health Genomics, The Genome Analysis Centre, Norwich NR18 7UH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186727" target="_blank"〉PubMed〈/a〉
    Keywords: Africa, Eastern ; Animals ; Cichlids/*classification/*genetics ; DNA Transposable Elements/genetics ; *Evolution, Molecular ; Gene Duplication/genetics ; Gene Expression Regulation/genetics ; *Genetic Speciation ; Genome/*genetics ; Genomics ; Lakes ; MicroRNAs/genetics ; Phylogeny ; Polymorphism, Genetic/genetics
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  • 70
    Publication Date: 2014-05-23
    Description: The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores (comb jellies) have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes, and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well recognized in ctenophores, many bilaterian neuron-specific genes and genes of 'classical' neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337882/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337882/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moroz, Leonid L -- Kocot, Kevin M -- Citarella, Mathew R -- Dosung, Sohn -- Norekian, Tigran P -- Povolotskaya, Inna S -- Grigorenko, Anastasia P -- Dailey, Christopher -- Berezikov, Eugene -- Buckley, Katherine M -- Ptitsyn, Andrey -- Reshetov, Denis -- Mukherjee, Krishanu -- Moroz, Tatiana P -- Bobkova, Yelena -- Yu, Fahong -- Kapitonov, Vladimir V -- Jurka, Jerzy -- Bobkov, Yuri V -- Swore, Joshua J -- Girardo, David O -- Fodor, Alexander -- Gusev, Fedor -- Sanford, Rachel -- Bruders, Rebecca -- Kittler, Ellen -- Mills, Claudia E -- Rast, Jonathan P -- Derelle, Romain -- Solovyev, Victor V -- Kondrashov, Fyodor A -- Swalla, Billie J -- Sweedler, Jonathan V -- Rogaev, Evgeny I -- Halanych, Kenneth M -- Kohn, Andrea B -- 1R01GM097502/GM/NIGMS NIH HHS/ -- 1S10RR027052/RR/NCRR NIH HHS/ -- 55007424/Howard Hughes Medical Institute/ -- 5R21DA030118/DA/NIDA NIH HHS/ -- P30 DA018310/DA/NIDA NIH HHS/ -- R01 AG029360/AG/NIA NIH HHS/ -- R01 GM097502/GM/NIGMS NIH HHS/ -- R01 MH097062/MH/NIMH NIH HHS/ -- R01MH097062/MH/NIMH NIH HHS/ -- R21 DA030118/DA/NIDA NIH HHS/ -- R21 RR025699/RR/NCRR NIH HHS/ -- R21RR025699/RR/NCRR NIH HHS/ -- S10 RR027052/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):109-14. doi: 10.1038/nature13400. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Whitney Laboratory for Marine Bioscience, University of Florida, 9505 Ocean Shore Blvd, St Augustine, Florida 32080, USA [2] Department of Neuroscience & McKnight Brain Institute, University of Florida, Gainesville, Florida 32611, USA [3] Friday Harbor Laboratories, University of Washington, Friday Harbor, Washington 98250, USA. ; Department of Biological Sciences, Auburn University, 101 Rouse Life Sciences, Auburn, Alabama 36849, USA. ; The Whitney Laboratory for Marine Bioscience, University of Florida, 9505 Ocean Shore Blvd, St Augustine, Florida 32080, USA. ; 1] The Whitney Laboratory for Marine Bioscience, University of Florida, 9505 Ocean Shore Blvd, St Augustine, Florida 32080, USA [2] Friday Harbor Laboratories, University of Washington, Friday Harbor, Washington 98250, USA. ; 1] Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain. ; 1] Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, Massachusetts 01604, USA [2] Vavilov Institute of General Genetics, Russian Academy of Sciences (RAS), Gubkina 3, Moscow 119991, Russia. ; Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA. ; European Research Institute for the Biology of Ageing, University of Groningen Medical Center, Antonius Deusinglaan 1, Building 3226, Room 03.34, 9713 AV Groningen, The Netherlands. ; Department of Medical Biophysics and Department of Immunology, University of Toronto, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. ; Vavilov Institute of General Genetics, Russian Academy of Sciences (RAS), Gubkina 3, Moscow 119991, Russia. ; Department of Neuroscience & McKnight Brain Institute, University of Florida, Gainesville, Florida 32611, USA. ; Genetic Information Research Institute, 1925 Landings Dr., Mountain View, California 94043, USA. ; Program in Molecular Medicine, University of Massachusetts Medical School, 222 Maple Avenue, Shrewsbury, Massachusetts 01545, USA. ; Friday Harbor Laboratories, University of Washington, Friday Harbor, Washington 98250, USA. ; Department of Computer Science, Royal Holloway, University of London, Egham, Surrey TW20 0EX, UK. ; 1] Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain [3] Institucio Catalana de Recerca i Estudis Avancats (ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain. ; 1] Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, Massachusetts 01604, USA [2] Vavilov Institute of General Genetics, Russian Academy of Sciences (RAS), Gubkina 3, Moscow 119991, Russia [3] Center for Brain Neurobiology and Neurogenetics and Institute of Cytology and Genetics, RAS, Lavrentyev Avenue, 10, Novosibirsk 630090, Russia [4] Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskiye Gory, 119991 Moscow, Russia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847885" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ctenophora/classification/*genetics/immunology/physiology ; *Evolution, Molecular ; Genes, Developmental ; Genes, Homeobox ; Genome/*genetics ; Mesoderm/metabolism ; Metabolomics ; MicroRNAs ; Molecular Sequence Data ; Muscles/physiology ; *Nervous System/metabolism ; Neurons/metabolism ; Neurotransmitter Agents ; Phylogeny ; Transcriptome/genetics
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  • 71
    Publication Date: 2014-08-15
    Description: Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the vertebrate brain. To gain a better understanding of how structural changes gate ion flux across the membrane, we trapped rat AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional states and analysed the resulting structures using cryo-electron microscopy. We show that transition to the active state involves a 'corkscrew' motion of the receptor assembly, driven by closure of the ligand-binding domain. Desensitization is accompanied by disruption of the amino-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry transition in the ligand-binding domains in both subtypes. The 7.6 A structure of a desensitized kainate receptor shows how these changes accommodate channel closing. These findings integrate previous physiological, biochemical and structural analyses of glutamate receptors and provide a molecular explanation for key steps in receptor gating.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199900/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199900/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meyerson, Joel R -- Kumar, Janesh -- Chittori, Sagar -- Rao, Prashant -- Pierson, Jason -- Bartesaghi, Alberto -- Mayer, Mark L -- Subramaniam, Sriram -- Z01 BC010278-10/Intramural NIH HHS/ -- ZIA BC010826-07/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 16;514(7522):328-34. doi: 10.1038/nature13603. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA. ; Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, Maryland 20892, USA. ; FEI Company, Hillsboro, Oregon 97124, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119039" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; *Cryoelectron Microscopy ; Glutamic Acid/chemistry/metabolism/pharmacology ; Ion Channel Gating/drug effects ; Ligands ; Models, Molecular ; Protein Structure, Tertiary/drug effects ; Rats ; Receptors, AMPA/antagonists & inhibitors/chemistry/*metabolism/*ultrastructure ; Receptors, Kainic Acid/chemistry/*metabolism/*ultrastructure
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  • 72
    Publication Date: 2014-04-22
    Description: The capacity of numerous bacterial species to tolerate antibiotics and other toxic compounds arises in part from the activity of energy-dependent transporters. In Gram-negative bacteria, many of these transporters form multicomponent 'pumps' that span both inner and outer membranes and are driven energetically by a primary or secondary transporter component. A model system for such a pump is the acridine resistance complex of Escherichia coli. This pump assembly comprises the outer-membrane channel TolC, the secondary transporter AcrB located in the inner membrane, and the periplasmic AcrA, which bridges these two integral membrane proteins. The AcrAB-TolC efflux pump is able to transport vectorially a diverse array of compounds with little chemical similarity, thus conferring resistance to a broad spectrum of antibiotics. Homologous complexes are found in many Gram-negative species, including in animal and plant pathogens. Crystal structures are available for the individual components of the pump and have provided insights into substrate recognition, energy coupling and the transduction of conformational changes associated with the transport process. However, how the subunits are organized in the pump, their stoichiometry and the details of their interactions are not known. Here we present the pseudo-atomic structure of a complete multidrug efflux pump in complex with a modulatory protein partner from E. coli. The model defines the quaternary organization of the pump, identifies key domain interactions, and suggests a cooperative process for channel assembly and opening. These findings illuminate the basis for drug resistance in numerous pathogenic bacterial species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361902/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361902/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Du, Dijun -- Wang, Zhao -- James, Nathan R -- Voss, Jarrod E -- Klimont, Ewa -- Ohene-Agyei, Thelma -- Venter, Henrietta -- Chiu, Wah -- Luisi, Ben F -- 076846/Wellcome Trust/United Kingdom -- 094229/Wellcome Trust/United Kingdom -- P41 GM103832/GM/NIGMS NIH HHS/ -- P41GM103832/GM/NIGMS NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 May 22;509(7501):512-5. doi: 10.1038/nature13205. Epub 2014 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. ; National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK. ; School of Pharmacy & Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia 5000, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24747401" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/metabolism ; Carrier Proteins/*chemistry/*metabolism ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Drug Resistance, Bacterial ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Lipoproteins/*chemistry/metabolism ; Membrane Transport Proteins/*chemistry/metabolism ; Models, Molecular ; Multidrug Resistance-Associated Proteins/*chemistry/*metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism
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  • 73
    Publication Date: 2014-08-19
    Description: Zinc is an essential micronutrient for all living organisms. It is required for signalling and proper functioning of a range of proteins involved in, for example, DNA binding and enzymatic catalysis. In prokaryotes and photosynthetic eukaryotes, Zn(2+)-transporting P-type ATPases of class IB (ZntA) are crucial for cellular redistribution and detoxification of Zn(2+) and related elements. Here we present crystal structures representing the phosphoenzyme ground state (E2P) and a dephosphorylation intermediate (E2.Pi) of ZntA from Shigella sonnei, determined at 3.2 A and 2.7 A resolution, respectively. The structures reveal a similar fold to Cu(+)-ATPases, with an amphipathic helix at the membrane interface. A conserved electronegative funnel connects this region to the intramembranous high-affinity ion-binding site and may promote specific uptake of cellular Zn(2+) ions by the transporter. The E2P structure displays a wide extracellular release pathway reaching the invariant residues at the high-affinity site, including C392, C394 and D714. The pathway closes in the E2.Pi state, in which D714 interacts with the conserved residue K693, which possibly stimulates Zn(2+) release as a built-in counter ion, as has been proposed for H(+)-ATPases. Indeed, transport studies in liposomes provide experimental support for ZntA activity without counter transport. These findings suggest a mechanistic link between PIB-type Zn(2+)-ATPases and PIII-type H(+)-ATPases and at the same time show structural features of the extracellular release pathway that resemble PII-type ATPases such as the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and Na(+), K(+)-ATPase. These findings considerably increase our understanding of zinc transport in cells and represent new possibilities for biotechnology and biomedicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259247/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259247/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Kaituo -- Sitsel, Oleg -- Meloni, Gabriele -- Autzen, Henriette Elisabeth -- Andersson, Magnus -- Klymchuk, Tetyana -- Nielsen, Anna Marie -- Rees, Douglas C -- Nissen, Poul -- Gourdon, Pontus -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 23;514(7523):518-22. doi: 10.1038/nature13618. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark [2] Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark (K.W. and P.G.); Department of Experimental Medical Science, Lund University, Solvegatan 19, SE-221 84 Lund, Sweden (P.G.). [3]. ; 1] Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark [2]. ; Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark. ; Science for Life Laboratory, Department of Theoretical Physics, Swedish e-Science Research Center, KTH Royal Institute of Technology, SE-171 21 Solna, Sweden. ; Division of Chemistry and Chemical Engineering and Howard Hughes Medical Institute, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA. ; 1] Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark [2] Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark (K.W. and P.G.); Department of Experimental Medical Science, Lund University, Solvegatan 19, SE-221 84 Lund, Sweden (P.G.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132545" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/*metabolism ; Adenosine Triphosphate/metabolism ; Binding Sites ; Cadmium/metabolism ; Calcium-Transporting ATPases/chemistry ; Conserved Sequence ; Crystallography, X-Ray ; Lead/metabolism ; Models, Molecular ; Phosphorylation ; Proteolipids/chemistry/metabolism ; Proton-Translocating ATPases/chemistry/metabolism ; Shigella/*enzymology ; Sodium-Potassium-Exchanging ATPase/chemistry ; Zinc/metabolism
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  • 74
    Publication Date: 2014-05-16
    Description: MicroRNA and protein sequestration by non-coding RNAs (ncRNAs) has recently generated much interest. In the bacterial Csr/Rsm system, which is considered to be the most general global post-transcriptional regulatory system responsible for bacterial virulence, ncRNAs such as CsrB or RsmZ activate translation initiation by sequestering homodimeric CsrA-type proteins from the ribosome-binding site of a subset of messenger RNAs. However, the mechanism of ncRNA-mediated protein sequestration is not understood at the molecular level. Here we show for Pseudomonas fluorescens that RsmE protein dimers assemble sequentially, specifically and cooperatively onto the ncRNA RsmZ within a narrow affinity range. This assembly yields two different native ribonucleoprotein structures. Using a powerful combination of nuclear magnetic resonance and electron paramagnetic resonance spectroscopy we elucidate these 70-kilodalton solution structures, thereby revealing the molecular mechanism of the sequestration process and how RsmE binding protects the ncRNA from RNase E degradation. Overall, our findings suggest that RsmZ is well-tuned to sequester, store and release RsmE and therefore can be viewed as an ideal protein 'sponge'.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duss, Olivier -- Michel, Erich -- Yulikov, Maxim -- Schubert, Mario -- Jeschke, Gunnar -- Allain, Frederic H-T -- England -- Nature. 2014 May 29;509(7502):588-92. doi: 10.1038/nature13271. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland. ; Laboratory of Physical Chemistry, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828038" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Electron Spin Resonance Spectroscopy ; Escherichia coli/chemistry/genetics/metabolism ; Escherichia coli Proteins/chemistry/*metabolism ; Methyltransferases/chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Molecular Weight ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; *Protein Binding ; Protein Multimerization ; RNA, Untranslated/chemistry/genetics/*metabolism ; Ribonucleases/metabolism ; Ribonucleoproteins/chemistry/genetics/metabolism
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  • 75
    Publication Date: 2014-01-10
    Description: The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif-CBF-beta-CUL5-ELOB-ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-beta, CUL5 and ELOC. The larger domain (alpha/beta domain) of Vif binds to the same side of CBF-beta as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-beta binding. Interactions of the smaller domain (alpha-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc-finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the alpha-domain, which may be important for Vif-CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Yingying -- Dong, Liyong -- Qiu, Xiaolin -- Wang, Yishu -- Zhang, Bailing -- Liu, Hongnan -- Yu, You -- Zang, Yi -- Yang, Maojun -- Huang, Zhiwei -- England -- Nature. 2014 Jan 9;505(7482):229-33. doi: 10.1038/nature12884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China [2]. ; School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China. ; MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402281" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Core Binding Factor Alpha 2 Subunit/metabolism ; Core Binding Factor beta Subunit/*chemistry/*metabolism ; Crystallography, X-Ray ; Cullin Proteins/*chemistry/*metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/metabolism ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; Suppressor of Cytokine Signaling Proteins ; Transcription Factors/chemistry/metabolism ; vif Gene Products, Human Immunodeficiency Virus/*chemistry/*metabolism
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  • 76
    Publication Date: 2014-06-10
    Description: Type-A gamma-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human beta3 homopentamer, at 3 A resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167603/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167603/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Paul S -- Aricescu, A Radu -- 084655/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- MR/L009609/1/Medical Research Council/United Kingdom -- England -- Nature. 2014 Aug 21;512(7514):270-5. doi: 10.1038/nature13293. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909990" target="_blank"〉PubMed〈/a〉
    Keywords: Benzamidines/chemistry/metabolism/pharmacology ; Binding Sites ; Cell Membrane/chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Drug Design ; GABA-A Receptor Agonists/chemistry/metabolism/pharmacology ; Genetic Predisposition to Disease ; Glycosylation ; Humans ; Models, Molecular ; Mutation/genetics ; Polysaccharides/chemistry/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits ; Receptors, GABA-A/*chemistry/genetics ; Synaptic Transmission
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  • 77
    Publication Date: 2014-06-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kutschera, U -- England -- Nature. 2014 Jun 12;510(7504):218. doi: 10.1038/510218a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biology, University of Kassel, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919913" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Hermaphroditic Organisms ; History, 20th Century ; Humans ; Phylogeny ; Selection, Genetic ; Women's Rights/*history
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  • 78
    Publication Date: 2014-04-30
    Description: Sensory proteins must relay structural signals from the sensory site over large distances to regulatory output domains. Phytochromes are a major family of red-light-sensing kinases that control diverse cellular functions in plants, bacteria and fungi. Bacterial phytochromes consist of a photosensory core and a carboxy-terminal regulatory domain. Structures of photosensory cores are reported in the resting state and conformational responses to light activation have been proposed in the vicinity of the chromophore. However, the structure of the signalling state and the mechanism of downstream signal relay through the photosensory core remain elusive. Here we report crystal and solution structures of the resting and activated states of the photosensory core of the bacteriophytochrome from Deinococcus radiodurans. The structures show an open and closed form of the dimeric protein for the activated and resting states, respectively. This nanometre-scale rearrangement is controlled by refolding of an evolutionarily conserved 'tongue', which is in contact with the chromophore. The findings reveal an unusual mechanism in which atomic-scale conformational changes around the chromophore are first amplified into an angstrom-scale distance change in the tongue, and further grow into a nanometre-scale conformational signal. The structural mechanism is a blueprint for understanding how phytochromes connect to the cellular signalling network.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015848/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takala, Heikki -- Bjorling, Alexander -- Berntsson, Oskar -- Lehtivuori, Heli -- Niebling, Stephan -- Hoernke, Maria -- Kosheleva, Irina -- Henning, Robert -- Menzel, Andreas -- Ihalainen, Janne A -- Westenhoff, Sebastian -- 1R24GM111072/GM/NIGMS NIH HHS/ -- 279944/European Research Council/International -- R24 GM111072/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 8;509(7499):245-8. doi: 10.1038/nature13310. Epub 2014 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Nanoscience Center, Department of Biological and Environmental Science, University of Jyvaskyla, 40014 Jyvaskyla, Finland [2] Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden [3]. ; 1] Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden [2]. ; Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden. ; Nanoscience Center, Department of Biological and Environmental Science, University of Jyvaskyla, 40014 Jyvaskyla, Finland. ; Center for Advanced Radiation Sources, The University of Chicago, Illinois 60637, USA. ; Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776794" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism/radiation effects ; Binding Sites ; Crystallography, X-Ray ; Deinococcus/*chemistry ; *Light Signal Transduction/radiation effects ; Models, Molecular ; Phytochrome/chemistry/metabolism/radiation effects ; Protein Conformation/radiation effects
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  • 79
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2014-02-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2014 Feb 13;506(7487):142-3. doi: 10.1038/506142a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24522580" target="_blank"〉PubMed〈/a〉
    Keywords: Asia/ethnology ; Child ; *Ethics, Research ; Genome, Human/*genetics ; Humans ; Indians, North American/classification/*genetics/psychology ; Male ; Montana ; Negotiating ; Phylogeny
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  • 80
    Publication Date: 2014-05-13
    Description: 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(epsilon)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066111/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066111/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chowdhury, Rasheduzzaman -- Sekirnik, Rok -- Brissett, Nigel C -- Krojer, Tobias -- Ho, Chia-Hua -- Ng, Stanley S -- Clifton, Ian J -- Ge, Wei -- Kershaw, Nadia J -- Fox, Gavin C -- Muniz, Joao R C -- Vollmar, Melanie -- Phillips, Claire -- Pilka, Ewa S -- Kavanagh, Kathryn L -- von Delft, Frank -- Oppermann, Udo -- McDonough, Michael A -- Doherty, Aidan J -- Schofield, Christopher J -- 092809/Wellcome Trust/United Kingdom -- 6947/Cancer Research UK/United Kingdom -- BB/C518230/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L009846/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Arthritis Research UK/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jun 19;510(7505):422-6. doi: 10.1038/nature13263. Epub 2014 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK. ; 1] The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK [2]. ; 1] Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK [2]. ; Structural Genomics Consortium, University of Oxford, Headington, Oxford OX3 7DQ, UK. ; Synchrotron SOLEIL, Saint Aubin, 91192 Gif-sur-Yvette Cedex, France. ; 1] Structural Genomics Consortium, University of Oxford, Headington, Oxford OX3 7DQ, UK [2] NIHR Oxford Biomedical Research Unit, Botnar Research Centre, Oxford OX3 7LD, UK. ; Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24814345" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Eukaryota/classification/*enzymology ; Humans ; *Models, Molecular ; Oxygenases/*chemistry/metabolism ; Phylogeny ; Prokaryotic Cells/classification/*enzymology ; Protein Folding ; Protein Structure, Tertiary ; Ribosomes/*enzymology ; Sequence Alignment
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  • 81
    Publication Date: 2014-10-31
    Description: Sponges are simple animals with few cell types, but their genomes paradoxically contain a wide variety of developmental transcription factors, including homeobox genes belonging to the Antennapedia (ANTP) class, which in bilaterians encompass Hox, ParaHox and NK genes. In the genome of the demosponge Amphimedon queenslandica, no Hox or ParaHox genes are present, but NK genes are linked in a tight cluster similar to the NK clusters of bilaterians. It has been proposed that Hox and ParaHox genes originated from NK cluster genes after divergence of sponges from the lineage leading to cnidarians and bilaterians. On the other hand, synteny analysis lends support to the notion that the absence of Hox and ParaHox genes in Amphimedon is a result of secondary loss (the ghost locus hypothesis). Here we analysed complete suites of ANTP-class homeoboxes in two calcareous sponges, Sycon ciliatum and Leucosolenia complicata. Our phylogenetic analyses demonstrate that these calcisponges possess orthologues of bilaterian NK genes (Hex, Hmx and Msx), a varying number of additional NK genes and one ParaHox gene, Cdx. Despite the generation of scaffolds spanning multiple genes, we find no evidence of clustering of Sycon NK genes. All Sycon ANTP-class genes are developmentally expressed, with patterns suggesting their involvement in cell type specification in embryos and adults, metamorphosis and body plan patterning. These results demonstrate that ParaHox genes predate the origin of sponges, thus confirming the ghost locus hypothesis, and highlight the need to analyse the genomes of multiple sponge lineages to obtain a complete picture of the ancestral composition of the first animal genome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fortunato, Sofia A V -- Adamski, Marcin -- Ramos, Olivia Mendivil -- Leininger, Sven -- Liu, Jing -- Ferrier, David E K -- Adamska, Maja -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2014 Oct 30;514(7524):620-3. doi: 10.1038/nature13881.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Sars International Centre for Marine Molecular Biology, University of Bergen, Thormohlensgate 55, 5008 Bergen, Norway [2] Department of Biology, University of Bergen, Thormohlensgate 55, 5008 Bergen, Norway. ; Sars International Centre for Marine Molecular Biology, University of Bergen, Thormohlensgate 55, 5008 Bergen, Norway. ; The Scottish Oceans Institute, Gatty Marine Laboratory, School of Biology, University of St Andrews, East Sands, St Andrews, Fife KY16 8LB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25355364" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Patterning/genetics ; Gene Expression Regulation ; Genes, Homeobox/*genetics ; Homeodomain Proteins/genetics ; Phylogeny ; Porifera/classification/cytology/*genetics/growth & development ; Synteny
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  • 82
    Publication Date: 2014-10-23
    Description: Bestrophin calcium-activated chloride channels (CaCCs) regulate the flow of chloride and other monovalent anions across cellular membranes in response to intracellular calcium (Ca(2+)) levels. Mutations in bestrophin 1 (BEST1) cause certain eye diseases. Here we present X-ray structures of chicken BEST1-Fab complexes, at 2.85 A resolution, with permeant anions and Ca(2+). Representing, to our knowledge, the first structure of a CaCC, the eukaryotic BEST1 channel, which recapitulates CaCC function in liposomes, is formed from a pentameric assembly of subunits. Ca(2+) binds to the channel's large cytosolic region. A single ion pore, approximately 95 A in length, is located along the central axis and contains at least 15 binding sites for anions. A hydrophobic neck within the pore probably forms the gate. Phenylalanine residues within it may coordinate permeating anions via anion-pi interactions. Conformational changes observed near the 'Ca(2+) clasp' hint at the mechanism of Ca(2+)-dependent gating. Disease-causing mutations are prevalent within the gating apparatus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454446/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454446/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kane Dickson, Veronica -- Pedi, Leanne -- Long, Stephen B -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM110396/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):213-8. doi: 10.1038/nature13913. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337878" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/analysis/chemistry/*metabolism/pharmacology ; *Chickens ; Chloride Channels/*chemistry/immunology/*metabolism ; Chlorides/chemistry/metabolism ; Crystallography, X-Ray ; Immunoglobulin Fab Fragments/chemistry/immunology ; Ion Channel Gating ; Ion Transport ; Liposomes/chemistry/metabolism ; Models, Molecular ; Structure-Activity Relationship
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  • 83
    Publication Date: 2014-01-10
    Description: The emergence of jawed vertebrates (gnathostomes) from jawless vertebrates was accompanied by major morphological and physiological innovations, such as hinged jaws, paired fins and immunoglobulin-based adaptive immunity. Gnathostomes subsequently diverged into two groups, the cartilaginous fishes and the bony vertebrates. Here we report the whole-genome analysis of a cartilaginous fish, the elephant shark (Callorhinchus milii). We find that the C. milii genome is the slowest evolving of all known vertebrates, including the 'living fossil' coelacanth, and features extensive synteny conservation with tetrapod genomes, making it a good model for comparative analyses of gnathostome genomes. Our functional studies suggest that the lack of genes encoding secreted calcium-binding phosphoproteins in cartilaginous fishes explains the absence of bone in their endoskeleton. Furthermore, the adaptive immune system of cartilaginous fishes is unusual: it lacks the canonical CD4 co-receptor and most transcription factors, cytokines and cytokine receptors related to the CD4 lineage, despite the presence of polymorphic major histocompatibility complex class II molecules. It thus presents a new model for understanding the origin of adaptive immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964593/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964593/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatesh, Byrappa -- Lee, Alison P -- Ravi, Vydianathan -- Maurya, Ashish K -- Lian, Michelle M -- Swann, Jeremy B -- Ohta, Yuko -- Flajnik, Martin F -- Sutoh, Yoichi -- Kasahara, Masanori -- Hoon, Shawn -- Gangu, Vamshidhar -- Roy, Scott W -- Irimia, Manuel -- Korzh, Vladimir -- Kondrychyn, Igor -- Lim, Zhi Wei -- Tay, Boon-Hui -- Tohari, Sumanty -- Kong, Kiat Whye -- Ho, Shufen -- Lorente-Galdos, Belen -- Quilez, Javier -- Marques-Bonet, Tomas -- Raney, Brian J -- Ingham, Philip W -- Tay, Alice -- Hillier, LaDeana W -- Minx, Patrick -- Boehm, Thomas -- Wilson, Richard K -- Brenner, Sydney -- Warren, Wesley C -- AI27877/AI/NIAID NIH HHS/ -- R01 AI027877/AI/NIAID NIH HHS/ -- R01 OD010549/OD/NIH HHS/ -- RR006603/RR/NCRR NIH HHS/ -- U41 HG002371/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Jan 9;505(7482):174-9. doi: 10.1038/nature12826.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673 [2] Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228. ; Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673. ; Developmental and Biomedical Genetics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673. ; Department of Developmental Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. ; Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland 21201, USA. ; Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. ; Molecular Engineering Laboratory, Biomedical Sciences Institutes, A*STAR, Biopolis, Singapore 138673. ; Department of Biology, San Francisco State University, San Francisco, California 94132, USA. ; Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Fish Developmental Biology Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673. ; 1] Institut de Biologia Evolutiva (UPF-CSIC), PRBB, 08003 Barcelona, Spain [2] Institucio Catalana de Recerca i Estudis Avancats (ICREA), 08010 Barcelona, Catalonia, Spain. ; Center for Biomolecular Science and Engineering, School of Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; The Genome Institute at Washington University, St Louis, Missouri 63108, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24402279" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Cell Lineage/immunology ; *Evolution, Molecular ; Fish Proteins/classification/genetics ; Gene Deletion ; Genome/*genetics ; Genomics ; Immunity, Cellular/genetics ; Molecular Sequence Annotation ; Molecular Sequence Data ; Osteogenesis/genetics ; Phosphoproteins/genetics/metabolism ; Phylogeny ; Protein Structure, Tertiary/genetics ; Sharks/*genetics/immunology ; T-Lymphocytes/cytology/immunology ; Time Factors ; Vertebrates/classification/genetics ; Zebrafish/genetics/growth & development
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  • 84
    Publication Date: 2014-03-05
    Description: Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ubn) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD). Non-covalent binding of K63-Ubn to 2CARD induces its tetramer formation, a requirement for downstream signal activation. Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub2. 2CARD assembles into a helical tetramer resembling a 'lock-washer', in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin-mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peisley, Alys -- Wu, Bin -- Xu, Hui -- Chen, Zhijian J -- Hur, Sun -- R01-GM63692/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 1;509(7498):110-4. doi: 10.1038/nature13140. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 USA [2] Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590070" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/metabolism ; Caspases/metabolism ; Crystallography, X-Ray ; DEAD-box RNA Helicases/*chemistry/*metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Protein Stability ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA, Viral/analysis/metabolism ; Signal Transduction ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin/*chemistry/*metabolism
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  • 85
    Publication Date: 2014-09-12
    Description: Complex I (NADH:ubiquinone oxidoreductase) is essential for oxidative phosphorylation in mammalian mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the energy-transducing inner membrane, providing electrons for respiration and driving ATP synthesis. Mammalian complex I contains 44 different nuclear- and mitochondrial-encoded subunits, with a combined mass of 1 MDa. The 14 conserved 'core' subunits have been structurally defined in the minimal, bacterial complex, but the structures and arrangement of the 30 'supernumerary' subunits are unknown. Here we describe a 5 A resolution structure of complex I from Bos taurus heart mitochondria, a close relative of the human enzyme, determined by single-particle electron cryo-microscopy. We present the structures of the mammalian core subunits that contain eight iron-sulphur clusters and 60 transmembrane helices, identify 18 supernumerary transmembrane helices, and assign and model 14 supernumerary subunits. Thus, we considerably advance knowledge of the structure of mammalian complex I and the architecture of its supernumerary ensemble around the core domains. Our structure provides insights into the roles of the supernumerary subunits in regulation, assembly and homeostasis, and a basis for understanding the effects of mutations that cause a diverse range of human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224586/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224586/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vinothkumar, Kutti R -- Zhu, Jiapeng -- Hirst, Judy -- MC_U105184322/Medical Research Council/United Kingdom -- MC_U105663141/Medical Research Council/United Kingdom -- U105184322/Medical Research Council/United Kingdom -- U105663141/Medical Research Council/United Kingdom -- England -- Nature. 2014 Nov 6;515(7525):80-4. doi: 10.1038/nature13686. Epub 2014 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK [2]. ; 1] MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK [2]. ; MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209663" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cattle ; Cryoelectron Microscopy ; Electron Transport Complex I/*chemistry/*ultrastructure ; Mitochondria, Heart/enzymology ; Models, Molecular ; Protein Structure, Tertiary ; Protein Subunits/chemistry
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  • 86
    Publication Date: 2014-10-04
    Description: The varied topography of human skin offers a unique opportunity to study how the body's microenvironments influence the functional and taxonomic composition of microbial communities. Phylogenetic marker gene-based studies have identified many bacteria and fungi that colonize distinct skin niches. Here metagenomic analyses of diverse body sites in healthy humans demonstrate that local biogeography and strong individuality define the skin microbiome. We developed a relational analysis of bacterial, fungal and viral communities, which showed not only site specificity but also individual signatures. We further identified strain-level variation of dominant species as heterogeneous and multiphyletic. Reference-free analyses captured the uncharacterized metagenome through the development of a multi-kingdom gene catalogue, which was used to uncover genetic signatures of species lacking reference genomes. This work is foundational for human disease studies investigating inter-kingdom interactions, metabolic changes and strain tracking, and defines the dual influence of biogeography and individuality on microbial composition and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185404/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185404/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oh, Julia -- Byrd, Allyson L -- Deming, Clay -- Conlan, Sean -- NISC Comparative Sequencing Program -- Kong, Heidi H -- Segre, Julia A -- 1K99AR059222/AR/NIAMS NIH HHS/ -- 1UH2AR057504-01/AR/NIAMS NIH HHS/ -- 4UH3AR057504-02/AR/NIAMS NIH HHS/ -- ZIA BC010938-06/Intramural NIH HHS/ -- ZIA HG000180-13/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 2;514(7520):59-64. doi: 10.1038/nature13786.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; 1] Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA [2]. ; 1] Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25279917" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/genetics/isolation & purification ; Female ; Genome, Bacterial/genetics ; Genome, Fungal/genetics ; Genome, Viral/genetics ; Genomics ; Healthy Volunteers ; Humans ; Male ; *Metagenome/genetics ; Phylogeny ; Propionibacterium acnes/genetics/isolation & purification/virology ; Skin/*microbiology/*virology ; Staphylococcus epidermidis/genetics/isolation & purification/virology ; Symbiosis
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  • 87
    Publication Date: 2014-12-24
    Description: Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation. Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to-order transitions upon binding to partners. Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function. In principle, the function of intrinsically disordered proteins may be controlled by post-translational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap-dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXLPhi motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site. We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a partly buried beta-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is weakly stable, decreasing affinity by 100-fold and leading to an order-to-disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bah, Alaji -- Vernon, Robert M -- Siddiqui, Zeba -- Krzeminski, Mickael -- Muhandiram, Ranjith -- Zhao, Charlie -- Sonenberg, Nahum -- Kay, Lewis E -- Forman-Kay, Julie D -- MOP-114985/Canadian Institutes of Health Research/Canada -- MOP-119579/Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 Mar 5;519(7541):106-9. doi: 10.1038/nature13999. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada [2] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada. ; 1] Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada [2] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533957" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Eukaryotic Initiation Factor-4E/*chemistry/*metabolism ; Eukaryotic Initiation Factors/*chemistry/*metabolism ; Humans ; Intrinsically Disordered Proteins/*chemistry/*metabolism ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Phosphorylation ; Protein Binding ; *Protein Folding ; Protein Structure, Secondary ; Signal Transduction
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  • 88
    Publication Date: 2014-07-22
    Description: Programmed -1 ribosomal frameshift (-1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a -1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated -1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA-miRNA interaction suggests that formation of a triplex RNA structure stimulates -1 PRF. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional -1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369343/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369343/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Belew, Ashton Trey -- Meskauskas, Arturas -- Musalgaonkar, Sharmishtha -- Advani, Vivek M -- Sulima, Sergey O -- Kasprzak, Wojciech K -- Shapiro, Bruce A -- Dinman, Jonathan D -- 5 R01GM058859/GM/NIGMS NIH HHS/ -- HHSN261200800001/PHS HHS/ -- R01 GM058859/GM/NIGMS NIH HHS/ -- R01 HL119439/HL/NHLBI NIH HHS/ -- R21 GM068123/GM/NIGMS NIH HHS/ -- R21GM068123/GM/NIGMS NIH HHS/ -- T32 AI051967/AI/NIAID NIH HHS/ -- T32AI051967/AI/NIAID NIH HHS/ -- T32GM080201/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Aug 21;512(7514):265-9. doi: 10.1038/nature13429. Epub 2014 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2]. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] Department of Biotechnology and Microbiology, Vilnius University, Vilnius, LT 03101, Lithuania [3]. ; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA. ; 1] Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA [2] VIB Center for the Biology of Disease, KU Leuven, Campus Gasthuisberg, Herestraat 49, bus 602, 3000 Leuven, Belgium. ; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Basic Research Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043019" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Binding Sites ; Cell Survival ; Codon, Nonsense/genetics ; Frameshifting, Ribosomal/*genetics ; HeLa Cells ; Humans ; MicroRNAs/*genetics ; Models, Molecular ; Molecular Sequence Data ; *Nonsense Mediated mRNA Decay ; Nucleic Acid Conformation ; RNA, Messenger/chemistry/*genetics/*metabolism ; Receptors, CCR5/*genetics ; Receptors, Interleukin/genetics ; Regulatory Sequences, Ribonucleic Acid ; Ribosomes/metabolism
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  • 89
    Publication Date: 2014-01-28
    Description: RNA-directed DNA methylation in Arabidopsis thaliana depends on the upstream synthesis of 24-nucleotide small interfering RNAs (siRNAs) by RNA POLYMERASE IV (Pol IV) and downstream synthesis of non-coding transcripts by Pol V. Pol V transcripts are thought to interact with siRNAs which then recruit DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) to methylate DNA. The SU(VAR)3-9 homologues SUVH2 and SUVH9 act in this downstream step but the mechanism of their action is unknown. Here we show that genome-wide Pol V association with chromatin redundantly requires SUVH2 and SUVH9. Although SUVH2 and SUVH9 resemble histone methyltransferases, a crystal structure reveals that SUVH9 lacks a peptide-substrate binding cleft and lacks a properly formed S-adenosyl methionine (SAM)-binding pocket necessary for normal catalysis, consistent with a lack of methyltransferase activity for these proteins. SUVH2 and SUVH9 both contain SRA (SET- and RING-ASSOCIATED) domains capable of binding methylated DNA, suggesting that they function to recruit Pol V through DNA methylation. Consistent with this model, mutation of DNA METHYLTRANSFERASE 1 (MET1) causes loss of DNA methylation, a nearly complete loss of Pol V at its normal locations, and redistribution of Pol V to sites that become hypermethylated. Furthermore, tethering SUVH2 with a zinc finger to an unmethylated site is sufficient to recruit Pol V and establish DNA methylation and gene silencing. These results indicate that Pol V is recruited to DNA methylation through the methyl-DNA binding SUVH2 and SUVH9 proteins, and our mechanistic findings suggest a means for selectively targeting regions of plant genomes for epigenetic silencing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963826/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, Lianna M -- Du, Jiamu -- Hale, Christopher J -- Bischof, Sylvain -- Feng, Suhua -- Chodavarapu, Ramakrishna K -- Zhong, Xuehua -- Marson, Giuseppe -- Pellegrini, Matteo -- Segal, David J -- Patel, Dinshaw J -- Jacobsen, Steven E -- F32GM096483-01/GM/NIGMS NIH HHS/ -- GM60398/GM/NIGMS NIH HHS/ -- P30 CA016042/CA/NCI NIH HHS/ -- R37 GM060398/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 6;507(7490):124-8. doi: 10.1038/nature12931. Epub 2014 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2]. ; Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA. ; 1] Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA [2] Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, California 90095, USA. ; 1] Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA [2] Wisconsin Institute for Discovery, Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA. ; Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Genome Center and Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463519" target="_blank"〉PubMed〈/a〉
    Keywords: *Arabidopsis/enzymology/genetics ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Binding Sites/genetics ; Biocatalysis ; Chromatin/chemistry/genetics/metabolism ; Crystallography, X-Ray ; DNA (Cytosine-5-)-Methyltransferase/genetics/metabolism ; *DNA Methylation/genetics ; DNA-Binding Proteins/chemistry/metabolism ; DNA-Directed RNA Polymerases/*metabolism ; Flowers/growth & development ; Gene Expression Regulation, Plant ; Gene Silencing ; Genome, Plant/genetics ; Histone-Lysine N-Methyltransferase/*chemistry/*metabolism ; Models, Molecular ; Mutation/genetics ; Phenotype ; Protein Structure, Tertiary ; Protein Transport ; RNA, Plant/biosynthesis/genetics/metabolism ; RNA, Small Interfering/biosynthesis/genetics/metabolism ; Transcription, Genetic ; Zinc Fingers
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  • 90
    Publication Date: 2014-11-05
    Description: T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Yu-Hwa -- Zhu, Chen -- Kondo, Yasuyuki -- Anderson, Ana C -- Gandhi, Amit -- Russell, Andrew -- Dougan, Stephanie K -- Petersen, Britt-Sabina -- Melum, Espen -- Pertel, Thomas -- Clayton, Kiera L -- Raab, Monika -- Chen, Qiang -- Beauchemin, Nicole -- Yazaki, Paul J -- Pyzik, Michal -- Ostrowski, Mario A -- Glickman, Jonathan N -- Rudd, Christopher E -- Ploegh, Hidde L -- Franke, Andre -- Petsko, Gregory A -- Kuchroo, Vijay K -- Blumberg, Richard S -- AI039671/AI/NIAID NIH HHS/ -- AI056299/AI/NIAID NIH HHS/ -- AI073748/AI/NIAID NIH HHS/ -- DK0034854/DK/NIDDK NIH HHS/ -- DK044319/DK/NIDDK NIH HHS/ -- DK051362/DK/NIDDK NIH HHS/ -- DK053056/DK/NIDDK NIH HHS/ -- DK088199/DK/NIDDK NIH HHS/ -- GM32415/GM/NIGMS NIH HHS/ -- MOP-93787/Canadian Institutes of Health Research/Canada -- NS045937/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI056299/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P30 DK034854/DK/NIDDK NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- R01 DK051362/DK/NIDDK NIH HHS/ -- R01 GM026788/GM/NIGMS NIH HHS/ -- R01 NS045937/NS/NINDS NIH HHS/ -- T32 GM007122/GM/NIGMS NIH HHS/ -- UL1 TR001102/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):386-90. doi: 10.1038/nature13848. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. ; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. ; Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA. ; Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany. ; 1] Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA [2] Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway. ; Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada. ; Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. ; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada. ; Beckman Institute, City of Hope, Duarte, California 91010, USA. ; 1] Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada [2] Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada. ; GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363763" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/immunology/*metabolism ; Autoimmunity/immunology ; Cell Adhesion Molecules/chemistry/immunology/*metabolism ; Cell Line ; Colorectal Neoplasms/immunology ; Disease Models, Animal ; Female ; Humans ; Immune Tolerance/*immunology ; Inflammation/immunology/pathology ; Ligands ; Male ; Membrane Proteins/chemistry/immunology/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Molecular ; Mucous Membrane/immunology/pathology ; Protein Conformation ; Protein Multimerization ; Receptors, Virus/chemistry/immunology/*metabolism ; T-Lymphocytes/*immunology/*metabolism
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  • 91
    Publication Date: 2014-07-22
    Description: The eukaryotic RNA exosome processes and degrades RNA by directing substrates to the distributive or processive 3' to 5' exoribonuclease activities of Rrp6 or Rrp44, respectively. The non-catalytic nine-subunit exosome core (Exo9) features a prominent central channel. Although RNA can pass through the channel to engage Rrp44, it is not clear how RNA is directed to Rrp6 or whether Rrp6 uses the central channel. Here we report a 3.3 A crystal structure of a ten-subunit RNA exosome complex from Saccharomyces cerevisiae composed of the Exo9 core and Rrp6 bound to single-stranded poly(A) RNA. The Rrp6 catalytic domain rests on top of the Exo9 S1/KH ring above the central channel, the RNA 3' end is anchored in the Rrp6 active site, and the remaining RNA traverses the S1/KH ring in an opposite orientation to that observed in a structure of a Rrp44-containing exosome complex. Solution studies with human and yeast RNA exosome complexes suggest that the RNA path to Rrp6 is conserved and dependent on the integrity of the S1/KH ring. Although path selection to Rrp6 or Rrp44 is stochastic in vitro, the fate of a particular RNA may be determined in vivo by the manner in which cofactors present RNA to the RNA exosome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310248/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310248/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wasmuth, Elizabeth V -- Januszyk, Kurt -- Lima, Christopher D -- F31 GM097910/GM/NIGMS NIH HHS/ -- F31GM097910/GM/NIGMS NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- P41GM103403/GM/NIGMS NIH HHS/ -- P41GM103473/GM/NIGMS NIH HHS/ -- R01 GM079196/GM/NIGMS NIH HHS/ -- R01GM079196/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 24;511(7510):435-9. doi: 10.1038/nature13406. Epub 2014 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Structural Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10065, USA [2] Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. ; Structural Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10065, USA. ; 1] Structural Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10065, USA [2] Howard Hughes Medical Institute, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043052" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; Exoribonucleases/metabolism ; Exosome Multienzyme Ribonuclease Complex/*chemistry/*metabolism ; Humans ; Models, Molecular ; Poly A/chemistry/*metabolism ; RNA, Messenger/*chemistry/*metabolism ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism
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  • 92
    Publication Date: 2014-10-31
    Description: The Polycomb group of epigenetic enzymes represses expression of developmentally regulated genes in many eukaryotes. This group includes the Polycomb repressive complex 1 (PRC1), which ubiquitylates nucleosomal histone H2A Lys 119 using its E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c. However, the molecular mechanism of nucleosome substrate recognition by PRC1 or other chromatin enzymes is unclear. Here we present the crystal structure of the human Ring1B-Bmi1-UbcH5c E3-E2 complex (the PRC1 ubiquitylation module) bound to its nucleosome core particle substrate. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. Our structure further reveals an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how the related histone H2A E3 ligase, BRCA1, interacts with and ubiquitylates the nucleosome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215650/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215650/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGinty, Robert K -- Henrici, Ryan C -- Tan, Song -- GM060489-09S1/GM/NIGMS NIH HHS/ -- GM088236/GM/NIGMS NIH HHS/ -- GM111651/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM060489/GM/NIGMS NIH HHS/ -- R01 GM088236/GM/NIGMS NIH HHS/ -- R01 GM111651/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):591-6. doi: 10.1038/nature13890.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Schreyer Honors College, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25355358" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; DNA/chemistry/metabolism ; Histones/chemistry/metabolism ; Humans ; Models, Molecular ; Nucleosomes/*chemistry/*metabolism ; Polycomb Repressive Complex 1/*chemistry/*metabolism ; Ubiquitin-Conjugating Enzymes/chemistry/metabolism ; Ubiquitin-Protein Ligases/chemistry/metabolism ; *Ubiquitination
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  • 93
    Publication Date: 2014-03-29
    Description: Large, actively swimming suspension feeders evolved several times in Earth's history, arising independently from groups as diverse as sharks, rays and stem teleost fishes, and in mysticete whales. However, animals occupying this niche have not been identified from the early Palaeozoic era. Anomalocarids, a group of stem arthropods that were the largest nektonic animals of the Cambrian and Ordovician periods, are generally thought to have been apex predators. Here we describe new material from Tamisiocaris borealis, an anomalocarid from the Early Cambrian (Series 2) Sirius Passet Fauna of North Greenland, and propose that its frontal appendage is specialized for suspension feeding. The appendage bears long, slender and equally spaced ventral spines furnished with dense rows of long and fine auxiliary spines. This suggests that T. borealis was a microphagous suspension feeder, using its appendages for sweep-net capture of food items down to 0.5 mm, within the size range of mesozooplankton such as copepods. Our observations demonstrate that large, nektonic suspension feeders first evolved during the Cambrian explosion, as part of an adaptive radiation of anomalocarids. The presence of nektonic suspension feeders in the Early Cambrian, together with evidence for a diverse pelagic community containing phytoplankton and mesozooplankton, indicate the existence of a complex pelagic ecosystem supported by high primary productivity and nutrient flux. Cambrian pelagic ecosystems seem to have been more modern than previously believed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vinther, Jakob -- Stein, Martin -- Longrich, Nicholas R -- Harper, David A T -- England -- Nature. 2014 Mar 27;507(7493):496-9. doi: 10.1038/nature13010.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Schools of Earth Sciences and Biological Sciences, University of Bristol, Woodland Road, Bristol BS8 1UG, UK. ; Natural History Museum of Denmark, Copenhagen University, Universitetsparken 15, 2100 , Denmark. ; Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK. ; Palaeoecosystems Group, Department of Earth Sciences, Durham University, Durham DH1 3LE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670770" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arthropods/anatomy & histology/classification/*physiology ; Biological Evolution ; Ecosystem ; Extinction, Biological ; Feeding Behavior/*physiology ; *Fossils ; Greenland ; Phylogeny ; Phytoplankton ; Zooplankton
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  • 94
    Publication Date: 2014-07-06
    Description: One of the fundamental properties of biological membranes is the asymmetric distribution of membrane lipids. In Gram-negative bacteria, the outer leaflet of the outer membrane is composed predominantly of lipopolysaccharides (LPS). The export of LPS requires seven essential lipopolysaccharide transport (Lpt) proteins to move LPS from the inner membrane, through the periplasm to the surface. Of the seven Lpt proteins, the LptD-LptE complex is responsible for inserting LPS into the external leaflet of the outer membrane. Here we report the crystal structure of the approximately 110-kilodalton membrane protein complex LptD-LptE from Shigella flexneri at 2.4 A resolution. The structure reveals an unprecedented two-protein plug-and-barrel architecture with LptE embedded into a 26-stranded beta-barrel formed by LptD. Importantly, the secondary structures of the first two beta-strands are distorted by two proline residues, weakening their interactions with neighbouring beta-strands and creating a potential portal on the barrel wall that could allow lateral diffusion of LPS into the outer membrane. The crystal structure of the LptD-LptE complex opens the door to new antibiotic strategies targeting the bacterial outer membrane.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qiao, Shuai -- Luo, Qingshan -- Zhao, Yan -- Zhang, Xuejun Cai -- Huang, Yihua -- England -- Nature. 2014 Jul 3;511(7507):108-11. doi: 10.1038/nature13484. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100101, China. ; 1] National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. ; National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990751" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/*metabolism ; Biological Transport ; Cell Membrane/chemistry/metabolism ; Crystallography, X-Ray ; Lipopolysaccharides/chemistry/*metabolism ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; Shigella flexneri/*chemistry/cytology
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  • 95
    Publication Date: 2014-09-16
    Description: Curli are functional amyloid fibres that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria (predominantly of the alpha and gamma classes). They provide a fitness advantage in pathogenic strains and induce a strong pro-inflammatory response during bacteraemia. Curli formation requires a dedicated protein secretion machinery comprising the outer membrane lipoprotein CsgG and two soluble accessory proteins, CsgE and CsgF. Here we report the X-ray structure of Escherichia coli CsgG in a non-lipidated, soluble form as well as in its native membrane-extracted conformation. CsgG forms an oligomeric transport complex composed of nine anticodon-binding-domain-like units that give rise to a 36-stranded beta-barrel that traverses the bilayer and is connected to a cage-like vestibule in the periplasm. The transmembrane and periplasmic domains are separated by a 0.9-nm channel constriction composed of three stacked concentric phenylalanine, asparagine and tyrosine rings that may guide the extended polypeptide substrate through the secretion pore. The specificity factor CsgE forms a nonameric adaptor that binds and closes off the periplasmic face of the secretion channel, creating a 24,000 A(3) pre-constriction chamber. Our structural, functional and electrophysiological analyses imply that CsgG is an ungated, non-selective protein secretion channel that is expected to employ a diffusion-based, entropy-driven transport mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268158/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268158/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goyal, Parveen -- Krasteva, Petya V -- Van Gerven, Nani -- Gubellini, Francesca -- Van den Broeck, Imke -- Troupiotis-Tsailaki, Anastassia -- Jonckheere, Wim -- Pehau-Arnaudet, Gerard -- Pinkner, Jerome S -- Chapman, Matthew R -- Hultgren, Scott J -- Howorka, Stefan -- Fronzes, Remi -- Remaut, Han -- R01 A1073847/PHS HHS/ -- R01 AI048689/AI/NIAID NIH HHS/ -- R01 AI073847/AI/NIAID NIH HHS/ -- R01 AI099099/AI/NIAID NIH HHS/ -- R56 AI073847/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):250-3. doi: 10.1038/nature13768. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium [2] Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. ; 1] Unite G5 Biologie structurale de la secretion bacterienne, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France [2] UMR 3528, CNRS, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France. ; Structure et Fonction des Membranes Biologiques (SFMB), Universite Libre de Bruxelles, 1050 Brussels, Belgium. ; UMR 3528, CNRS, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France. ; Department of Molecular Microbiology and Microbial Pathogenesis, Washington University in Saint Louis School of Medicine, St Louis, Missouri 63110-1010, USA. ; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1048, USA. ; Department of Chemistry, Institute for Structural and Molecular Biology, University College London, London WC1H 0AJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219853" target="_blank"〉PubMed〈/a〉
    Keywords: Amyloid/*secretion ; Biofilms ; Cell Membrane ; Crystallography, X-Ray ; Diffusion ; Entropy ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Lipoproteins/*chemistry/*metabolism ; Membrane Transport Proteins/metabolism ; Models, Biological ; Models, Molecular ; Periplasm/metabolism ; Protein Conformation ; Protein Transport
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  • 96
    Publication Date: 2014-08-01
    Description: Liver cirrhosis occurs as a consequence of many chronic liver diseases that are prevalent worldwide. Here we characterize the gut microbiome in liver cirrhosis by comparing 98 patients and 83 healthy control individuals. We build a reference gene set for the cohort containing 2.69 million genes, 36.1% of which are novel. Quantitative metagenomics reveals 75,245 genes that differ in abundance between the patients and healthy individuals (false discovery rate 〈 0.0001) and can be grouped into 66 clusters representing cognate bacterial species; 28 are enriched in patients and 38 in control individuals. Most (54%) of the patient-enriched, taxonomically assigned species are of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis. Biomarkers specific to liver cirrhosis at gene and function levels are revealed by a comparison with those for type 2 diabetes and inflammatory bowel disease. On the basis of only 15 biomarkers, a highly accurate patient discrimination index is created and validated on an independent cohort. Thus microbiota-targeted biomarkers may be a powerful tool for diagnosis of different diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Nan -- Yang, Fengling -- Li, Ang -- Prifti, Edi -- Chen, Yanfei -- Shao, Li -- Guo, Jing -- Le Chatelier, Emmanuelle -- Yao, Jian -- Wu, Lingjiao -- Zhou, Jiawei -- Ni, Shujun -- Liu, Lin -- Pons, Nicolas -- Batto, Jean Michel -- Kennedy, Sean P -- Leonard, Pierre -- Yuan, Chunhui -- Ding, Wenchao -- Chen, Yuanting -- Hu, Xinjun -- Zheng, Beiwen -- Qian, Guirong -- Xu, Wei -- Ehrlich, S Dusko -- Zheng, Shusen -- Li, Lanjuan -- England -- Nature. 2014 Sep 4;513(7516):59-64. doi: 10.1038/nature13568. Epub 2014 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, 310003 Hangzhou, China [3]. ; 1] State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China [2]. ; 1] Metagenopolis, Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France [2]. ; State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China. ; Metagenopolis, Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France. ; 1] State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, 310003 Hangzhou, China. ; 1] Metagenopolis, Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France [2] King's College London, Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy's Hospital, London Bridge, London SE1 9RT, UK. ; 1] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, 310003 Hangzhou, China [2] Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University, 310003 Hangzhou, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079328" target="_blank"〉PubMed〈/a〉
    Keywords: Case-Control Studies ; Chronic Disease ; Diabetes Mellitus, Type 2/microbiology ; Feces/microbiology ; Gastrointestinal Tract/*microbiology ; Genetic Markers/genetics ; Health ; Humans ; Inflammatory Bowel Diseases/microbiology ; Liver Cirrhosis/*diagnosis/*microbiology ; *Metagenomics ; Microbiota/*genetics/*physiology ; Mouth/microbiology ; Phylogeny ; Reproducibility of Results
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  • 97
    Publication Date: 2014-11-20
    Description: The influenza virus polymerase transcribes or replicates the segmented RNA genome (viral RNA) into viral messenger RNA or full-length copies. To initiate RNA synthesis, the polymerase binds to the conserved 3' and 5' extremities of the viral RNA. Here we present the crystal structure of the heterotrimeric bat influenza A polymerase, comprising subunits PA, PB1 and PB2, bound to its viral RNA promoter. PB1 contains a canonical RNA polymerase fold that is stabilized by large interfaces with PA and PB2. The PA endonuclease and the PB2 cap-binding domain, involved in transcription by cap-snatching, form protrusions facing each other across a solvent channel. The 5' extremity of the promoter folds into a compact hook that is bound in a pocket formed by PB1 and PA close to the polymerase active site. This structure lays the basis for an atomic-level mechanistic understanding of the many functions of influenza polymerase, and opens new opportunities for anti-influenza drug design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pflug, Alexander -- Guilligay, Delphine -- Reich, Stefan -- Cusack, Stephen -- England -- Nature. 2014 Dec 18;516(7531):355-60. doi: 10.1038/nature14008. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France [2] University Grenoble Alpes-Centre National de la Recherche Scientifique-EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409142" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallization ; DNA-Directed RNA Polymerases/*chemistry ; Influenza A virus/*enzymology ; Models, Molecular ; Promoter Regions, Genetic ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; RNA, Viral/*chemistry
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  • 98
    Publication Date: 2014-02-28
    Description: Tripartite Tc toxin complexes of bacterial pathogens perforate the host membrane and translocate toxic enzymes into the host cell, including in humans. The underlying mechanism is complex but poorly understood. Here we report the first, to our knowledge, high-resolution structures of a TcA subunit in its prepore and pore state and of a complete 1.7 megadalton Tc complex. The structures reveal that, in addition to a translocation channel, TcA forms four receptor-binding sites and a neuraminidase-like region, which are important for its host specificity. pH-induced opening of the shell releases an entropic spring that drives the injection of the TcA channel into the membrane. Binding of TcB/TcC to TcA opens a gate formed by a six-bladed beta-propeller and results in a continuous protein translocation channel, whose architecture and properties suggest a novel mode of protein unfolding and translocation. Our results allow us to understand key steps of infections involving Tc toxins at the molecular level.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meusch, Dominic -- Gatsogiannis, Christos -- Efremov, Rouslan G -- Lang, Alexander E -- Hofnagel, Oliver -- Vetter, Ingrid R -- Aktories, Klaus -- Raunser, Stefan -- England -- Nature. 2014 Apr 3;508(7494):61-5. doi: 10.1038/nature13015. Epub 2014 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany [2]. ; Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany. ; Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; 1] Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany. ; 1] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany [2] Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Thielallee 63, 14195 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572368" target="_blank"〉PubMed〈/a〉
    Keywords: ADP Ribose Transferases/metabolism ; Bacterial Toxins/*chemistry/*metabolism ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Host Specificity ; Hydrogen-Ion Concentration ; Models, Molecular ; Neuraminidase/chemistry ; Photorhabdus/*chemistry ; Porosity ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protein Transport ; Protein Unfolding ; Structure-Activity Relationship
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  • 99
    Publication Date: 2014-02-21
    Description: Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide. HCV infection often results in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. No vaccine is available and current therapies are effective against some, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies. Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an antigen-binding fragment (Fab) at 2.4 A resolution. The E2 core has a compact, globular domain structure, consisting mostly of beta-strands and random coil with two small alpha-helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulphide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins, whereas sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements on exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126800/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126800/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khan, Abdul Ghafoor -- Whidby, Jillian -- Miller, Matthew T -- Scarborough, Hannah -- Zatorski, Alexandra V -- Cygan, Alicja -- Price, Aryn A -- Yost, Samantha A -- Bohannon, Caitlin D -- Jacob, Joshy -- Grakoui, Arash -- Marcotrigiano, Joseph -- AI070101/AI/NIAID NIH HHS/ -- DK083356/DK/NIDDK NIH HHS/ -- P50 GM103368/GM/NIGMS NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- P51 RR000165/RR/NCRR NIH HHS/ -- R01 AI070101/AI/NIAID NIH HHS/ -- R01 AI080659/AI/NIAID NIH HHS/ -- R01 DK083356/DK/NIDDK NIH HHS/ -- RR-00165/RR/NCRR NIH HHS/ -- T32 AI007403/AI/NIAID NIH HHS/ -- T32 AI007610/AI/NIAID NIH HHS/ -- England -- Nature. 2014 May 15;509(7500):381-4. doi: 10.1038/nature13117. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA. ; Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA. ; 1] Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA [2] Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553139" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Disulfides/chemistry ; Hepacivirus/*chemistry/physiology ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin Fab Fragments/chemistry/metabolism ; Immunoglobulin G/chemistry ; Models, Molecular ; Protein Folding ; Protein Structure, Tertiary ; Scattering, Small Angle ; Surface Properties ; Viral Envelope Proteins/*chemistry/metabolism ; Viral Fusion Proteins ; Viral Hepatitis Vaccines ; Virus Internalization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
    Publication Date: 2014-02-14
    Description: The assembly of 30S ribosomes requires the precise addition of 20 proteins to the 16S ribosomal RNA. How early binding proteins change the ribosomal RNA structure so that later proteins may join the complex is poorly understood. Here we use single-molecule fluorescence resonance energy transfer (FRET) to observe real-time encounters between Escherichia coli ribosomal protein S4 and the 16S 5' domain RNA at an early stage of 30S assembly. Dynamic initial S4-RNA complexes pass through a stable non-native intermediate before converting to the native complex, showing that non-native structures can offer a low free-energy path to protein-RNA recognition. Three-colour FRET and molecular dynamics simulations reveal how S4 changes the frequency and direction of RNA helix motions, guiding a conformational switch that enforces the hierarchy of protein addition. These protein-guided dynamics offer an alternative explanation for induced fit in RNA-protein complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hajin -- Abeysirigunawarden, Sanjaya C -- Chen, Ke -- Mayerle, Megan -- Ragunathan, Kaushik -- Luthey-Schulten, Zaida -- Ha, Taekjip -- Woodson, Sarah A -- R01 GM060819/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- R01 GM60819/GM/NIGMS NIH HHS/ -- R01 GM65367/GM/NIGMS NIH HHS/ -- T32 GM007231/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Feb 20;506(7488):334-8. doi: 10.1038/nature13039. Epub 2014 Feb 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Howard Hughes Medical Institute, Urbana, Illinois 61801, USA [3] [4] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] T. C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2]. ; 1] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] CMDB Program, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Howard Hughes Medical Institute, Urbana, Illinois 61801, USA [3] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [4] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] T. C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2] CMDB Program, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24522531" target="_blank"〉PubMed〈/a〉
    Keywords: Escherichia coli/chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Kinetics ; Models, Molecular ; *Molecular Dynamics Simulation ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; RNA, Ribosomal, 16S/*chemistry/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; Ribosomal Proteins/chemistry/*metabolism ; Ribosome Subunits, Small, Bacterial/*chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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