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  • Crystallography, X-Ray  (74)
  • Chemistry
  • Industrial Chemistry
  • Inorganic Chemistry
  • MASERS
  • Nature Publishing Group (NPG)  (77)
  • 2010-2014  (77)
  • 1960-1964
  • 1950-1954
  • 1930-1934
  • 1915-1919
  • 2013  (77)
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  • 2010-2014  (77)
  • 1960-1964
  • 1950-1954
  • 1930-1934
  • 1915-1919
Year
  • 1
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    X-ray structure of the mammalian GIRK2-betagamma G-protein complex (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-07
    Description: G-protein-gated inward rectifier K(+) (GIRK) channels allow neurotransmitters, through G-protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity, respectively. Here we present the 3.5 A resolution crystal structure of the mammalian GIRK2 channel in complex with betagamma G-protein subunits, the central signalling complex that links G-protein-coupled receptor stimulation to K(+) channel activity. Short-range atomic and long-range electrostatic interactions stabilize four betagamma G-protein subunits at the interfaces between four K(+) channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with 'membrane delimited' activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signalling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) and intracellular Na(+) ions participate in multi-ligand regulation of GIRK channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654628/" 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/PMC4654628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whorton, Matthew R -- MacKinnon, Roderick -- 1S10RR022321-01/RR/NCRR NIH HHS/ -- 1S10RR027037-01/RR/NCRR NIH HHS/ -- S10 RR027037/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 13;498(7453):190-7. doi: 10.1038/nature12241. Epub 2013 Jun 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, 1230 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/23739333" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; G Protein-Coupled Inwardly-Rectifying Potassium ; Channels/*chemistry/genetics/metabolism ; Heterotrimeric GTP-Binding Proteins/*chemistry/genetics/metabolism ; Humans ; Ion Channel Gating ; Models, Biological ; Models, Molecular ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Subunits/chemistry/metabolism ; Sodium/metabolism ; Static Electricity
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  • 2
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    Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1 (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-03
    Description: DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24-nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119789/" 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/PMC4119789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Law, Julie A -- Du, Jiamu -- Hale, Christopher J -- Feng, Suhua -- Krajewski, Krzysztof -- Palanca, Ana Marie S -- Strahl, Brian D -- Patel, Dinshaw J -- Jacobsen, Steven E -- GM60398/GM/NIGMS NIH HHS/ -- GM85394/GM/NIGMS NIH HHS/ -- R01 GM060398/GM/NIGMS NIH HHS/ -- R37 GM060398/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 20;498(7454):385-9. doi: 10.1038/nature12178. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636332" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*enzymology/genetics/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Binding Sites/genetics ; Chromatin/chemistry/genetics/metabolism ; Crystallography, X-Ray ; DNA Methylation/*genetics ; DNA-Directed RNA Polymerases/genetics/*metabolism ; Epigenesis, Genetic/genetics ; Histones/chemistry/metabolism ; Homeodomain Proteins/chemistry/*metabolism ; Lysine/chemistry/metabolism ; Methyltransferases/genetics/metabolism ; Models, Molecular ; Mutation ; Protein Folding ; Protein Structure, Tertiary ; RNA, Small Interfering/biosynthesis/genetics/metabolism
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  • 3
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    The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-05
    Description: The contraction and relaxation of muscle cells is controlled by the successive rise and fall of cytosolic Ca(2+), initiated by the release of Ca(2+) from the sarcoplasmic reticulum and terminated by re-sequestration of Ca(2+) into the sarcoplasmic reticulum as the main mechanism of Ca(2+) removal. Re-sequestration requires active transport and is catalysed by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), which has a key role in defining the contractile properties of skeletal and heart muscle tissue. The activity of SERCA is regulated by two small, homologous membrane proteins called phospholamban (PLB, also known as PLN) and sarcolipin (SLN). Detailed structural information explaining this regulatory mechanism has been lacking, and the structural features defining the pathway through which cytoplasmic Ca(2+) enters the intramembranous binding sites of SERCA have remained unknown. Here we report the crystal structure of rabbit SERCA1a (also known as ATP2A1) in complex with SLN at 3.1 A resolution. The regulatory SLN traps the Ca(2+)-ATPase in a previously undescribed E1 state, with exposure of the Ca(2+) sites through an open cytoplasmic pathway stabilized by Mg(2+). The structure suggests a mechanism for selective Ca(2+) loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca(2+). These findings may prove useful in studying how autoinhibitory domains of other ion pumps modulate transport across biological membranes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winther, Anne-Marie L -- Bublitz, Maike -- Karlsen, Jesper L -- Moller, Jesper V -- Hansen, John B -- Nissen, Poul -- Buch-Pedersen, Morten J -- England -- Nature. 2013 Mar 14;495(7440):265-9. doi: 10.1038/nature11900. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Pcovery, Thorvaldsensvej 57, DK-1871 Frederiksberg, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455424" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/*metabolism ; Calcium-Binding Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Cytoplasm/*metabolism ; Enzyme Activation ; Magnesium/metabolism ; Models, Molecular ; Muscle Proteins/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Proteolipids/chemistry/*metabolism ; Rabbits ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*chemistry/*metabolism
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  • 4
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    Structural basis for the drug extrusion mechanism by a MATE multidrug transporter (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-29
    Description: Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H(+) or Na(+) across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H(+)-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1-3.0 A resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanaka, Yoshiki -- Hipolito, Christopher J -- Maturana, Andres D -- Ito, Koichi -- Kuroda, Teruo -- Higuchi, Takashi -- Katoh, Takayuki -- Kato, Hideaki E -- Hattori, Motoyuki -- Kumazaki, Kaoru -- Tsukazaki, Tomoya -- Ishitani, Ryuichiro -- Suga, Hiroaki -- Nureki, Osamu -- England -- Nature. 2013 Apr 11;496(7444):247-51. doi: 10.1038/nature12014. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535598" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antiporters/*chemistry/*metabolism ; Apoproteins/chemistry/metabolism ; Archaeal Proteins/*chemistry/*metabolism ; Aspartic Acid/chemistry ; Crystallography, X-Ray ; DNA Mutational Analysis ; Macrocyclic Compounds/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Norfloxacin/chemistry/metabolism ; Peptides/chemistry/metabolism ; Protein Conformation ; Protons ; Pyrococcus furiosus/*chemistry ; Structure-Activity Relationship ; Sulfides/chemistry/metabolism
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  • 5
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    Structure of class B GPCR corticotropin-releasing factor receptor 1 (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-19
    Description: Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hollenstein, Kaspar -- Kean, James -- Bortolato, Andrea -- Cheng, Robert K Y -- Dore, Andrew S -- Jazayeri, Ali -- Cooke, Robert M -- Weir, Malcolm -- Marshall, Fiona H -- England -- Nature. 2013 Jul 25;499(7459):438-43. doi: 10.1038/nature12357. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863939" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Aminopyridines/chemistry/metabolism/pharmacology ; Binding Sites ; Conserved Sequence ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/*chemistry/*classification/metabolism ; Receptors, Dopamine D3/antagonists & inhibitors/chemistry/classification
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  • 6
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    Unusual base pairing during the decoding of a stop codon by the ribosome (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-03
    Description: During normal translation, the binding of a release factor to one of the three stop codons (UGA, UAA or UAG) results in the termination of protein synthesis. However, modification of the initial uridine to a pseudouridine (Psi) allows efficient recognition and read-through of these stop codons by a transfer RNA (tRNA), although it requires the formation of two normally forbidden purine-purine base pairs. Here we determined the crystal structure at 3.1 A resolution of the 30S ribosomal subunit in complex with the anticodon stem loop of tRNA(Ser) bound to the PsiAG stop codon in the A site. The PsiA base pair at the first position is accompanied by the formation of purine-purine base pairs at the second and third positions of the codon, which show an unusual Watson-Crick/Hoogsteen geometry. The structure shows a previously unsuspected ability of the ribosomal decoding centre to accommodate non-canonical base pairs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732562/" 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/PMC3732562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez, Israel S -- Ng, Chyan Leong -- Kelley, Ann C -- Wu, Guowei -- Yu, Yi-Tao -- Ramakrishnan, V -- 096570/Wellcome Trust/United Kingdom -- GM104077/GM/NIGMS NIH HHS/ -- MC_U105184332/Medical Research Council/United Kingdom -- R01 GM104077/GM/NIGMS NIH HHS/ -- R21 AG039559/AG/NIA NIH HHS/ -- U105184332/Medical Research Council/United Kingdom -- England -- Nature. 2013 Aug 1;500(7460):107-10. doi: 10.1038/nature12302. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812587" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/chemistry/genetics/metabolism ; *Base Pairing ; Base Sequence ; Codon, Terminator/chemistry/*genetics/*metabolism ; Crystallography, X-Ray ; Models, Molecular ; Nucleic Acid Conformation ; Protein Conformation ; Pseudouridine/chemistry/genetics/metabolism ; RNA, Transfer, Ser/chemistry/genetics/metabolism ; Ribosome Subunits, Small, Bacterial/chemistry/genetics/metabolism ; Ribosomes/*chemistry/genetics/*metabolism
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  • 7
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    Crystal structure of the integral membrane diacylglycerol kinase (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-17
    Description: Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740270/" 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/PMC3740270/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Dianfan -- Lyons, Joseph A -- Pye, Valerie E -- Vogeley, Lutz -- Aragao, David -- Kenyon, Colin P -- Shah, Syed T A -- Doherty, Christine -- Aherne, Margaret -- Caffrey, Martin -- GM75915/GM/NIGMS NIH HHS/ -- P41 RR015301/RR/NCRR NIH HHS/ -- P50GM073210/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- U54GM094599/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):521-4. doi: 10.1038/nature12179. Epub 2013 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23676677" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Bacterial Proteins/*chemistry/genetics/metabolism ; Catalytic Domain ; Cell Membrane/*metabolism ; Crystallography, X-Ray ; Diacylglycerol Kinase/*chemistry/genetics/*metabolism ; Enzyme Activation/drug effects ; Enzyme Stability ; Lipids ; Magnesium/metabolism ; Membrane Proteins/*chemistry/genetics/metabolism ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Conformation ; Zinc/pharmacology
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  • 8
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    Structural insight into the biogenesis of beta-barrel membrane proteins (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-03
    Description: beta-barrel membrane proteins are essential for nutrient import, signalling, motility and survival. In Gram-negative bacteria, the beta-barrel assembly machinery (BAM) complex is responsible for the biogenesis of beta-barrel membrane proteins, with homologous complexes found in mitochondria and chloroplasts. Here we describe the structure of BamA, the central and essential component of the BAM complex, from two species of bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. BamA consists of a large periplasmic domain attached to a 16-strand transmembrane beta-barrel domain. Three structural features shed light on the mechanism by which BamA catalyses beta-barrel assembly. First, the interior cavity is accessible in one BamA structure and conformationally closed in the other. Second, an exterior rim of the beta-barrel has a distinctly narrowed hydrophobic surface, locally destabilizing the outer membrane. And third, the beta-barrel can undergo lateral opening, suggesting a route from the interior cavity in BamA into the outer membrane.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779476/" 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/PMC3779476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Noinaj, Nicholas -- Kuszak, Adam J -- Gumbart, James C -- Lukacik, Petra -- Chang, Hoshing -- Easley, Nicole C -- Lithgow, Trevor -- Buchanan, Susan K -- K22 AI100927/AI/NIAID NIH HHS/ -- K22-AI100927/AI/NIAID NIH HHS/ -- R01 GM067887/GM/NIGMS NIH HHS/ -- R01-GM67887/GM/NIGMS NIH HHS/ -- RC2GM093307/GM/NIGMS NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- ZIA DK036139-06/Intramural NIH HHS/ -- England -- Nature. 2013 Sep 19;501(7467):385-90. doi: 10.1038/nature12521. Epub 2013 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995689" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*biosynthesis/*chemistry/genetics ; Cell Membrane/chemistry/metabolism ; Crystallography, X-Ray ; Escherichia coli/chemistry/genetics ; Escherichia coli Proteins/chemistry/genetics ; Haemophilus/*chemistry ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Mutagenesis ; Neisseria gonorrhoeae/*chemistry ; Protein Conformation ; Structural Homology, Protein
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    Crystal structure of the 14-subunit RNA polymerase I (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-25
    Description: Protein biosynthesis depends on the availability of ribosomes, which in turn relies on ribosomal RNA production. In eukaryotes, this process is carried out by RNA polymerase I (Pol I), a 14-subunit enzyme, the activity of which is a major determinant of cell growth. Here we present the crystal structure of Pol I from Saccharomyces cerevisiae at 3.0 A resolution. The Pol I structure shows a compact core with a wide DNA-binding cleft and a tightly anchored stalk. An extended loop mimics the DNA backbone in the cleft and may be involved in regulating Pol I transcription. Subunit A12.2 extends from the A190 jaw to the active site and inserts a transcription elongation factor TFIIS-like zinc ribbon into the nucleotide triphosphate entry pore, providing insight into the role of A12.2 in RNA cleavage and Pol I insensitivity to alpha-amanitin. The A49-A34.5 heterodimer embraces subunit A135 through extended arms, thereby contacting and potentially regulating subunit A12.2.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez-Tornero, Carlos -- Moreno-Morcillo, Maria -- Rashid, Umar J -- Taylor, Nicholas M I -- Ruiz, Federico M -- Gruene, Tim -- Legrand, Pierre -- Steuerwald, Ulrich -- Muller, Christoph W -- England -- Nature. 2013 Oct 31;502(7473):644-9. doi: 10.1038/nature12636. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040 Madrid, Spain [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153184" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; Models, Molecular ; Peptide Chain Elongation, Translational ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Subunits/*chemistry ; RNA Polymerase I/*chemistry ; RNA Polymerase II/chemistry ; RNA Polymerase III/chemistry ; Saccharomyces cerevisiae/*enzymology ; Transcription, Genetic
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    Structural basis of histone H2A-H2B recognition by the essential chaperone FACT (2013)
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    Publication Date: 2013-05-24
    Description: Facilitates chromatin transcription (FACT) is a conserved histone chaperone that reorganizes nucleosomes and ensures chromatin integrity during DNA transcription, replication and repair. Key to the broad functions of FACT is its recognition of histones H2A-H2B (ref. 2). However, the structural basis for how histones H2A-H2B are recognized and how this integrates with the other functions of FACT, including the recognition of histones H3-H4 and other nuclear factors, is unknown. Here we reveal the crystal structure of the evolutionarily conserved FACT chaperone domain Spt16M from Chaetomium thermophilum, in complex with the H2A-H2B heterodimer. A novel 'U-turn' motif scaffolded onto a Rtt106-like module embraces the alpha1 helix of H2B. Biochemical and in vivo assays validate the structure and dissect the contribution of histone tails and H3-H4 towards Spt16M binding. Furthermore, we report the structure of the FACT heterodimerization domain that connects FACT to replicative polymerases. Our results show that Spt16M makes several interactions with histones, which we suggest allow the module to invade the nucleosome gradually and block the strongest interaction of H2B with DNA. FACT would thus enhance 'nucleosome breathing' by re-organizing the first 30 base pairs of nucleosomal histone-DNA contacts. Our snapshot of the engagement of the chaperone with H2A-H2B and the structures of all globular FACT domains enable the high-resolution analysis of the vital chaperoning functions of FACT, shedding light on how the complex promotes the activity of enzymes that require nucleosome reorganization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hondele, Maria -- Stuwe, Tobias -- Hassler, Markus -- Halbach, Felix -- Bowman, Andrew -- Zhang, Elisa T -- Nijmeijer, Bianca -- Kotthoff, Christiane -- Rybin, Vladimir -- Amlacher, Stefan -- Hurt, Ed -- Ladurner, Andreas G -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 4;499(7456):111-4. doi: 10.1038/nature12242. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Butenandt Institute and LMU Biomedical Center, Faculty of Medicine, Ludwig Maximilians University of Munich, Butenandtstrasse 5, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698368" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Chaetomium/*chemistry ; Conserved Sequence ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA Replication ; Fungal Proteins/*chemistry/*metabolism ; Histones/chemistry/*metabolism ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Chaperones/*chemistry/*metabolism ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Substrate Specificity
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    Femtosecond switching of magnetism via strongly correlated spin-charge quantum excitations (2013)
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    Publication Date: 2013-04-05
    Description: The technological demand to push the gigahertz (10(9) hertz) switching speed limit of today's magnetic memory and logic devices into the terahertz (10(12) hertz) regime underlies the entire field of spin-electronics and integrated multi-functional devices. This challenge is met by all-optical magnetic switching based on coherent spin manipulation. By analogy to femtosecond chemistry and photosynthetic dynamics--in which photoproducts of chemical and biochemical reactions can be influenced by creating suitable superpositions of molecular states--femtosecond-laser-excited coherence between electronic states can switch magnetic order by 'suddenly' breaking the delicate balance between competing phases of correlated materials: for example, manganites exhibiting colossal magneto-resistance suitable for applications. Here we show femtosecond (10(-15) seconds) photo-induced switching from antiferromagnetic to ferromagnetic ordering in Pr0.7Ca0.3MnO3, by observing the establishment (within about 120 femtoseconds) of a huge temperature-dependent magnetization with photo-excitation threshold behaviour absent in the optical reflectivity. The development of ferromagnetic correlations during the femtosecond laser pulse reveals an initial quantum coherent regime of magnetism, distinguished from the picosecond (10(-12) seconds) lattice-heating regime characterized by phase separation without threshold behaviour. Our simulations reproduce the nonlinear femtosecond spin generation and underpin fast quantum spin-flip fluctuations correlated with coherent superpositions of electronic states to initiate local ferromagnetic correlations. These results merge two fields, femtosecond magnetism in metals and band insulators, and non-equilibrium phase transitions of strongly correlated electrons, in which local interactions exceeding the kinetic energy produce a complex balance of competing orders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Tianqi -- Patz, Aaron -- Mouchliadis, Leonidas -- Yan, Jiaqiang -- Lograsso, Thomas A -- Perakis, Ilias E -- Wang, Jigang -- England -- Nature. 2013 Apr 4;496(7443):69-73. doi: 10.1038/nature11934.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics and Astronomy, Iowa State University, Ames, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552945" target="_blank"〉PubMed〈/a〉
    Keywords: Biology ; Chemistry ; Circular Dichroism ; Electronics ; Iron/chemistry ; *Magnetic Phenomena ; Magnetics ; Optics and Photonics ; Photosynthesis ; *Quantum Theory ; Temperature ; Time Factors
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    Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors (2013)
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    Publication Date: 2013-11-15
    Description: Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, David J -- St Jean, David J Jr -- Kurzeja, Robert J M -- Wahl, Robert C -- Michelsen, Klaus -- Cupples, Rod -- Chen, Michelle -- Wu, John -- Sivits, Glenn -- Helmering, Joan -- Komorowski, Renee -- Ashton, Kate S -- Pennington, Lewis D -- Fotsch, Christopher -- Vazir, Mukta -- Chen, Kui -- Chmait, Samer -- Zhang, Jiandong -- Liu, Longbin -- Norman, Mark H -- Andrews, Kristin L -- Bartberger, Michael D -- Van, Gwyneth -- Galbreath, Elizabeth J -- Vonderfecht, Steven L -- Wang, Minghan -- Jordan, Steven R -- Veniant, Murielle M -- Hale, Clarence -- England -- Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Comparative Biology & Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226772" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology ; Disease Models, Animal ; Hepatocytes ; Humans ; Hyperglycemia/blood/drug therapy/enzymology ; Hypoglycemic Agents/chemistry/*pharmacology/*therapeutic use ; Liver/cytology/enzymology/metabolism ; Male ; Models, Molecular ; Organ Specificity ; Phosphorylation/drug effects ; Piperazines/chemistry/metabolism/pharmacology/therapeutic use ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
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    SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket (2013)
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    Publication Date: 2013-03-19
    Description: The cryptochrome (CRY) flavoproteins act as blue-light receptors in plants and insects, but perform light-independent functions at the core of the mammalian circadian clock. To drive clock oscillations, mammalian CRYs associate with the Period proteins (PERs) and together inhibit the transcription of their own genes. The SCF(FBXL3) ubiquitin ligase complex controls this negative feedback loop by promoting CRY ubiquitination and degradation. However, the molecular mechanisms of their interactions and the functional role of flavin adenine dinucleotide (FAD) binding in CRYs remain poorly understood. Here we report crystal structures of mammalian CRY2 in its apo, FAD-bound and FBXL3-SKP1-complexed forms. Distinct from other cryptochromes of known structures, mammalian CRY2 binds FAD dynamically with an open cofactor pocket. Notably, the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface. This novel F-box-protein-substrate bipartite interaction is susceptible to disruption by both FAD and PERs, suggesting a new avenue for pharmacological targeting of the complex and a multifaceted regulatory mechanism of CRY ubiquitination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618506/" 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/PMC3618506/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xing, Weiman -- Busino, Luca -- Hinds, Thomas R -- Marionni, Samuel T -- Saifee, Nabiha H -- Bush, Matthew F -- Pagano, Michele -- Zheng, Ning -- 5T32-HL007151/HL/NHLBI NIH HHS/ -- K99 CA166181/CA/NCI NIH HHS/ -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01-CA107134/CA/NCI NIH HHS/ -- R01-GM057587/GM/NIGMS NIH HHS/ -- R21-CA161108/CA/NCI NIH HHS/ -- R37 CA076584/CA/NCI NIH HHS/ -- R37-CA-076584/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 4;496(7443):64-8. doi: 10.1038/nature11964. Epub 2013 Mar 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23503662" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoproteins/chemistry/metabolism ; Binding Sites ; Cryptochromes/chemistry/*metabolism ; Crystallography, X-Ray ; Deoxyribodipyrimidine Photo-Lyase/chemistry ; Drosophila melanogaster/chemistry ; F-Box Proteins/chemistry/*metabolism ; Flavin-Adenine Dinucleotide/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Models, Molecular ; Protein Structure, Tertiary ; S-Phase Kinase-Associated Proteins/chemistry/metabolism ; SKP Cullin F-Box Protein Ligases/chemistry/*metabolism ; Substrate Specificity
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    Receptor binding by a ferret-transmissible H5 avian influenza virus (2013)
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    Publication Date: 2013-04-26
    Description: Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA-receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiong, Xiaoli -- Coombs, Peter J -- Martin, Stephen R -- Liu, Junfeng -- Xiao, Haixia -- McCauley, John W -- Locher, Kathrin -- Walker, Philip A -- Collins, Patrick J -- Kawaoka, Yoshihiro -- Skehel, John J -- Gamblin, Steven J -- BB/E010806/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U117512723/Medical Research Council/United Kingdom -- MC_U117584222/Medical Research Council/United Kingdom -- U117512723/Medical Research Council/United Kingdom -- U117570592/Medical Research Council/United Kingdom -- U117584222/Medical Research Council/United Kingdom -- England -- Nature. 2013 May 16;497(7449):392-6. doi: 10.1038/nature12144. Epub 2013 Apr 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23615615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/metabolism/virology ; Chick Embryo ; Crystallography, X-Ray ; Ferrets/*virology ; Hemagglutinin Glycoproteins, Influenza Virus/*chemistry/genetics/*metabolism ; *Host Specificity ; Humans ; Influenza A Virus, H5N1 Subtype/chemistry/*genetics/*metabolism/pathogenicity ; Models, Biological ; Models, Molecular ; Mutation ; Orthomyxoviridae Infections/*transmission/*virology ; Protein Conformation ; Receptors, Virus/*metabolism ; Species Specificity
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    Structural mechanism of cytosolic DNA sensing by cGAS (2013)
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    Publication Date: 2013-06-01
    Description: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" 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/PMC3768140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Civril, Filiz -- Deimling, Tobias -- de Oliveira Mann, Carina C -- Ablasser, Andrea -- Moldt, Manuela -- Witte, Gregor -- Hornung, Veit -- Hopfner, Karl-Peter -- 243046/European Research Council/International -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):332-7. doi: 10.1038/nature12305. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/metabolism ; Animals ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; *Cytosol ; DNA/chemistry/*metabolism/pharmacology ; Guanosine Triphosphate/chemistry/metabolism ; HEK293 Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mice ; Models, Biological ; Models, Molecular ; Mutation ; Nucleotidyltransferases/*chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Structure-Activity Relationship ; Substrate Specificity ; Swine ; Uridine Triphosphate/chemistry/metabolism ; Zinc/chemistry/metabolism
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    The initiation of mammalian protein synthesis and mRNA scanning mechanism (2013)
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    Publication Date: 2013-07-23
    Description: During translation initiation in eukaryotes, the small ribosomal subunit binds messenger RNA at the 5' end and scans in the 5' to 3' direction to locate the initiation codon, form the 80S initiation complex and start protein synthesis. This simple, yet intricate, process is guided by multiple initiation factors. Here we determine the structures of three complexes of the small ribosomal subunit that represent distinct steps in mammalian translation initiation. These structures reveal the locations of eIF1, eIF1A, mRNA and initiator transfer RNA bound to the small ribosomal subunit and provide insights into the details of translation initiation specific to eukaryotes. Conformational changes associated with the captured functional states reveal the dynamics of the interactions in the P site of the ribosome. These results have functional implications for the mechanism of mRNA scanning.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748252/" 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/PMC3748252/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lomakin, Ivan B -- Steitz, Thomas A -- GM022778/GM/NIGMS NIH HHS/ -- P01 GM022778/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Aug 15;500(7462):307-11. doi: 10.1038/nature12355. Epub 2013 Jul 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, USA. ivan.lomakin@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23873042" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Eukaryotic Initiation Factor-1/chemistry/metabolism ; Humans ; *Models, Molecular ; Protein Binding ; *Protein Biosynthesis ; Protein Structure, Quaternary ; RNA, Messenger/*chemistry/*metabolism ; RNA, Transfer, Met/chemistry/metabolism ; Rabbits ; Ribosome Subunits, Small, Eukaryotic/chemistry/metabolism ; Ribosomes/metabolism
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    Structural basis for the modular recognition of single-stranded RNA by PPR proteins (2013)
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    Publication Date: 2013-10-29
    Description: Pentatricopeptide repeat (PPR) proteins represent a large family of sequence-specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism. PPR proteins, which are found in exceptionally large numbers in the mitochondria and chloroplasts of terrestrial plants, recognize single-stranded RNA (ssRNA) in a modular fashion. The maize chloroplast protein PPR10 binds to two similar RNA sequences from the ATPI-ATPH and PSAJ-RPL33 intergenic regions, referred to as ATPH and PSAJ, respectively. By protecting the target RNA elements from 5' or 3' exonucleases, PPR10 defines the corresponding 5' and 3' messenger RNA termini. Despite rigorous functional characterizations, the structural basis of sequence-specific ssRNA recognition by PPR proteins remains to be elucidated. Here we report the crystal structures of PPR10 in RNA-free and RNA-bound states at resolutions of 2.85 and 2.45 A, respectively. In the absence of RNA binding, the nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms an antiparallel, intertwined homodimer and exhibits considerable conformational changes upon binding to its target ssRNA, an 18-nucleotide PSAJ element. Six nucleotides of PSAJ are specifically recognized by six corresponding PPR10 repeats following the predicted code. The molecular basis for the specific and modular recognition of RNA bases A, G and U is revealed. The structural elucidation of RNA recognition by PPR proteins provides an important framework for potential biotechnological applications of PPR proteins in RNA-related research areas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Ping -- Li, Quanxiu -- Yan, Chuangye -- Liu, Ying -- Liu, Junjie -- Yu, Feng -- Wang, Zheng -- Long, Jiafu -- He, Jianhua -- Wang, Hong-Wei -- Wang, Jiawei -- Zhu, Jian-Kang -- Shi, Yigong -- Yan, Nieng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 5;504(7478):168-71. doi: 10.1038/nature12651. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162847" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; *Models, Molecular ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; Zea mays/*chemistry/genetics/metabolism
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  • 18
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    Carbon catabolite repression of the maltose transporter revealed by X-ray crystallography (2013)
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    Publication Date: 2013-06-19
    Description: Efficient carbon utilization is critical to the survival of microorganisms in competitive environments. To optimize energy usage, bacteria have developed an integrated control system to preferentially uptake carbohydrates that support rapid growth. The availability of a preferred carbon source, such as glucose, represses the synthesis and activities of proteins necessary for the transport and metabolism of secondary carbon sources. This regulatory phenomenon is defined as carbon catabolite repression. In enteric bacteria, the key player of carbon catabolite repression is a component of the glucose-specific phosphotransferase system, enzyme IIA (EIIA(Glc)). It is known that unphosphorylated EIIA(Glc) binds to and inhibits a variety of transporters when glucose is available. However, understanding the underlying molecular mechanism has been hindered by the complete absence of structures for any EIIA(Glc)-transporter complexes. Here we present the 3.9 A crystal structure of Escherichia coli EIIA(Glc) in complex with the maltose transporter, an ATP-binding cassette (ABC) transporter. The structure shows that two EIIA(Glc) molecules bind to the cytoplasmic ATPase subunits, stabilizing the transporter in an inward-facing conformation and preventing the structural rearrangements necessary for ATP hydrolysis. We also show that the half-maximal inhibitory concentrations of the full-length EIIA(Glc) and an amino-terminal truncation mutant differ by 60-fold, consistent with the hypothesis that the amino-terminal region, disordered in the crystal structure, functions as a membrane anchor to increase the effective EIIA(Glc) concentration at the membrane. Together these data suggest a model of how the central regulatory protein EIIA(Glc) allosterically inhibits maltose uptake in E. coli.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875231/" 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/PMC3875231/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Shanshuang -- Oldham, Michael L -- Davidson, Amy L -- Chen, Jue -- GM070515/GM/NIGMS NIH HHS/ -- R01 GM070515/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 18;499(7458):364-8. doi: 10.1038/nature12232. Epub 2013 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23770568" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/metabolism ; Carbon/metabolism ; Crystallography, X-Ray ; Escherichia coli Proteins/*chemistry/metabolism ; Models, Molecular ; Phosphoenolpyruvate Sugar Phosphotransferase System/*chemistry/metabolism
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    Crystal structure of the entire respiratory complex I (2013)
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    Publication Date: 2013-02-19
    Description: Complex I is the first and largest enzyme of the respiratory chain and has a central role in cellular energy production through the coupling of NADH:ubiquinone electron transfer to proton translocation. It is also implicated in many common human neurodegenerative diseases. Here, we report the first crystal structure of the entire, intact complex I (from Thermus thermophilus) at 3.3 A resolution. The structure of the 536-kDa complex comprises 16 different subunits, with a total of 64 transmembrane helices and 9 iron-sulphur clusters. The core fold of subunit Nqo8 (ND1 in humans) is, unexpectedly, similar to a half-channel of the antiporter-like subunits. Small subunits nearby form a linked second half-channel, which completes the fourth proton-translocation pathway (present in addition to the channels in three antiporter-like subunits). The quinone-binding site is unusually long, narrow and enclosed. The quinone headgroup binds at the deep end of this chamber, near iron-sulphur cluster N2. Notably, the chamber is linked to the fourth channel by a 'funnel' of charged residues. The link continues over the entire membrane domain as a flexible central axis of charged and polar residues, and probably has a leading role in the propagation of conformational changes, aided by coupling elements. The structure suggests that a unique, out-of-the-membrane quinone-reaction chamber enables the redox energy to drive concerted long-range conformational changes in the four antiporter-like domains, resulting in translocation of four protons per cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672946/" 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/PMC3672946/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baradaran, Rozbeh -- Berrisford, John M -- Minhas, Gurdeep S -- Sazanov, Leonid A -- MC_U105674180/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Feb 28;494(7438):443-8. doi: 10.1038/nature11871. Epub 2013 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council 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/23417064" target="_blank"〉PubMed〈/a〉
    Keywords: Benzoquinones/chemistry/metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; NAD/metabolism ; Oxidation-Reduction ; Protein Folding ; Protein Subunits/chemistry/metabolism ; Proton-Motive Force ; Protons ; Thermus thermophilus/*chemistry/cytology ; Ubiquinone/metabolism
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    SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine (2013)
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    Publication Date: 2013-04-05
    Description: The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human SIRT6 efficiently removes long-chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of SIRT6 reveals a large hydrophobic pocket that can accommodate long-chain fatty acyl groups. We demonstrate further that SIRT6 promotes the secretion of tumour necrosis factor-alpha (TNF-alpha) by removing the fatty acyl modification on K19 and K20 of TNF-alpha. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data indicate that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of SIRT6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of a protein post-translational modification that has been little studied until now.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635073/" 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/PMC3635073/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Hong -- Khan, Saba -- Wang, Yi -- Charron, Guillaume -- He, Bin -- Sebastian, Carlos -- Du, Jintang -- Kim, Ray -- Ge, Eva -- Mostoslavsky, Raul -- Hang, Howard C -- Hao, Quan -- Lin, Hening -- R01 CA175727/CA/NCI NIH HHS/ -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM086703/GM/NIGMS NIH HHS/ -- R01 GM087544/GM/NIGMS NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- R01GM086703/GM/NIGMS NIH HHS/ -- R01GM087544/GM/NIGMS NIH HHS/ -- R01GM093072/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 4;496(7443):110-3. doi: 10.1038/nature12038.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552949" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Binding Sites ; Crystallography, X-Ray ; Fatty Acids/*chemistry/*metabolism ; Humans ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Lysine/*analogs & derivatives/chemistry/*metabolism ; Protein Processing, Post-Translational ; Sirtuins/chemistry/*metabolism ; Tumor Necrosis Factor-alpha/chemistry/metabolism/*secretion
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    Structure of the human smoothened receptor bound to an antitumour agent (2013)
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    Publication Date: 2013-05-03
    Description: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657389/" 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/PMC3657389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Chong -- Wu, Huixian -- Katritch, Vsevolod -- Han, Gye Won -- Huang, Xi-Ping -- Liu, Wei -- Siu, Fai Yiu -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 16;497(7449):338-43. doi: 10.1038/nature12167. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636324" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Antineoplastic Agents/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry ; Frizzled Receptors/chemistry/classification ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Phthalazines/*chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry/classification/metabolism ; Structural Homology, Protein
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    Structural basis for action by diverse antidepressants on biogenic amine transporters (2013)
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    Publication Date: 2013-10-15
    Description: The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" 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/PMC3904662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Hui -- Goehring, April -- Wang, Kevin H -- Penmatsa, Aravind -- Ressler, Ryan -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):141-5. doi: 10.1038/nature12648. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum 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/24121440" target="_blank"〉PubMed〈/a〉
    Keywords: Antidepressive Agents, Second-Generation/metabolism/*pharmacology ; Antidepressive Agents, Tricyclic/metabolism/*pharmacology ; Bacterial Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Binding, Competitive/drug effects ; Biogenic Amines/*metabolism ; Chlorides/metabolism ; Crystallography, X-Ray ; Humans ; Mazindol/metabolism/pharmacology ; Models, Molecular ; Mutation ; Norepinephrine/metabolism ; *Plasma Membrane Neurotransmitter Transport Proteins/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Recombinant Fusion Proteins/*chemistry/genetics/metabolism ; Reproducibility of Results ; Serotonin Plasma Membrane Transport Proteins/*chemistry/genetics/*metabolism ; Serotonin Uptake Inhibitors/metabolism/*pharmacology ; Sertraline/metabolism/pharmacology ; Sodium/metabolism ; Structure-Activity Relationship
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    Molecular signatures of G-protein-coupled receptors (2013)
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    Publication Date: 2013-02-15
    Description: G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatakrishnan, A J -- Deupi, Xavier -- Lebon, Guillaume -- Tate, Christopher G -- Schertler, Gebhard F -- Babu, M Madan -- MC_U105185859/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- U105185859/Medical Research Council/United Kingdom -- U105197215/Medical Research Council/United Kingdom -- England -- Nature. 2013 Feb 14;494(7436):185-94. doi: 10.1038/nature11896.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. ajv@mrc-lmb.cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23407534" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Humans ; Ligands ; Protein Conformation ; Protein Folding ; Receptors, G-Protein-Coupled/agonists/antagonists & ; inhibitors/*chemistry/*metabolism ; Signal Transduction
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    Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids (2013)
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    Publication Date: 2013-07-19
    Description: Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2alpha (cPLA2alpha), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, alpha-helically-dominated 'sandwich' topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2alpha release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951269/" 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/PMC3951269/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simanshu, Dhirendra K -- Kamlekar, Ravi Kanth -- Wijesinghe, Dayanjan S -- Zou, Xianqiong -- Zhai, Xiuhong -- Mishra, Shrawan K -- Molotkovsky, Julian G -- Malinina, Lucy -- Hinchcliffe, Edward H -- Chalfant, Charles E -- Brown, Rhoderick E -- Patel, Dinshaw J -- CA121493/CA/NCI NIH HHS/ -- CA154314/CA/NCI NIH HHS/ -- GM072754/GM/NIGMS NIH HHS/ -- GM45928/GM/NIGMS NIH HHS/ -- I01 BX001792/BX/BLRD VA/ -- R01 CA121493/CA/NCI NIH HHS/ -- R01 CA154314/CA/NCI NIH HHS/ -- R01 GM045928/GM/NIGMS NIH HHS/ -- R01 GM072754/GM/NIGMS NIH HHS/ -- R01 HL072925/HL/NHLBI NIH HHS/ -- S10 OD010641/OD/NIH HHS/ -- T32 008695/PHS HHS/ -- England -- Nature. 2013 Aug 22;500(7463):463-7. doi: 10.1038/nature12332. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863933" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoproteins/chemistry ; Arachidonic Acid/metabolism ; Biological Transport ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Membrane/metabolism ; Cell Nucleus/metabolism ; Ceramides/chemistry/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Eicosanoids/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Models, Molecular ; Phosphatidic Acids/chemistry/metabolism ; Protein Conformation ; Protein Folding ; Substrate Specificity ; trans-Golgi Network/metabolism
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    Precision is essential for efficient catalysis in an evolved Kemp eliminase (2013)
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    Publication Date: 2013-10-18
    Description: Linus Pauling established the conceptual framework for understanding and mimicking enzymes more than six decades ago. The notion that enzymes selectively stabilize the rate-limiting transition state of the catalysed reaction relative to the bound ground state reduces the problem of design to one of molecular recognition. Nevertheless, past attempts to capitalize on this idea, for example by using transition state analogues to elicit antibodies with catalytic activities, have generally failed to deliver true enzymatic rates. The advent of computational design approaches, combined with directed evolution, has provided an opportunity to revisit this problem. Starting from a computationally designed catalyst for the Kemp elimination--a well-studied model system for proton transfer from carbon--we show that an artificial enzyme can be evolved that accelerates an elementary chemical reaction 6 x 10(8)-fold, approaching the exceptional efficiency of highly optimized natural enzymes such as triosephosphate isomerase. A 1.09 A resolution crystal structure of the evolved enzyme indicates that familiar catalytic strategies such as shape complementarity and precisely placed catalytic groups can be successfully harnessed to afford such high rate accelerations, making us optimistic about the prospects of designing more sophisticated catalysts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blomberg, Rebecca -- Kries, Hajo -- Pinkas, Daniel M -- Mittl, Peer R E -- Grutter, Markus G -- Privett, Heidi K -- Mayo, Stephen L -- Hilvert, Donald -- England -- Nature. 2013 Nov 21;503(7476):418-21. doi: 10.1038/nature12623. Epub 2013 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Organic Chemistry, ETH Zurich, 8093 Zurich, Switzerland [2] Corporate RD Division, Firmenich SA, 1211 Geneva, Switzerland (R.B.); Protabit, Pasadena, California 91101, USA (H.K.P.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24132235" target="_blank"〉PubMed〈/a〉
    Keywords: *Biocatalysis ; Carbon/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; *Directed Molecular Evolution ; Enzymes/*chemistry/genetics/*metabolism ; Kinetics ; Models, Molecular ; *Protein Engineering ; Protons ; Triazoles/chemistry/metabolism ; Triose-Phosphate Isomerase/metabolism
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    Chemistry: A festive ferment (2013)
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    Publication Date: 2013-12-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGee, Harold -- England -- Nature. 2013 Dec 19;504(7480):372-4. doi: 10.1038/504372a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24352277" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aspergillus/metabolism ; Beer/microbiology ; Cheese/microbiology ; Chemistry ; *Fermentation ; *Food Technology ; Microbiology ; Saccharomyces cerevisiae/metabolism
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    Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-17
    Description: The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/" 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/PMC3895326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jungwook -- Xiao, Hui -- Bonanno, Jeffrey B -- Kalyanaraman, Chakrapani -- Brown, Shoshana -- Tang, Xiangying -- Al-Obaidi, Nawar F -- Patskovsky, Yury -- Babbitt, Patricia C -- Jacobson, Matthew P -- Lee, Young-Sam -- Almo, Steven C -- GM093342/GM/NIGMS NIH HHS/ -- GM094662/GM/NIGMS NIH HHS/ -- P30-EB-009998/EB/NIBIB NIH HHS/ -- U54 GM093342/GM/NIGMS NIH HHS/ -- U54 GM094662/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jun 6;498(7452):123-6. doi: 10.1038/nature12180. Epub 2013 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA. jungwook.kim@einstein.yu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23676670" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Biosynthetic Pathways ; Catalytic Domain ; Crystallography, X-Ray ; Cyclohexanecarboxylic Acids/metabolism ; Cyclohexenes/metabolism ; Escherichia coli/enzymology ; Escherichia coli Proteins/chemistry/genetics/*metabolism ; Ligands ; Methyltransferases/deficiency/genetics/*metabolism ; Models, Molecular ; Molecular Weight ; One-Carbon Group Transferases/chemistry/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; RNA, Bacterial/chemistry/genetics/metabolism ; RNA, Transfer/chemistry/*genetics/*metabolism ; S-Adenosylmethionine/*analogs & derivatives/biosynthesis/*chemistry/*metabolism ; Uridine/analogs & derivatives/chemistry/metabolism
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    Icosahedral bacteriophage PhiX174 forms a tail for DNA transport during infection (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-12-18
    Description: Prokaryotic viruses have evolved various mechanisms to transport their genomes across bacterial cell walls. Many bacteriophages use a tail to perform this function, whereas tail-less phages rely on host organelles. However, the tail-less, icosahedral, single-stranded DNA PhiX174-like coliphages do not fall into these well-defined infection processes. For these phages, DNA delivery requires a DNA pilot protein. Here we show that the PhiX174 pilot protein H oligomerizes to form a tube whose function is most probably to deliver the DNA genome across the host's periplasmic space to the cytoplasm. The 2.4 A resolution crystal structure of the in vitro assembled H protein's central domain consists of a 170 A-long alpha-helical barrel. The tube is constructed of ten alpha-helices with their amino termini arrayed in a right-handed super-helical coiled-coil and their carboxy termini arrayed in a left-handed super-helical coiled-coil. Genetic and biochemical studies demonstrate that the tube is essential for infectivity but does not affect in vivo virus assembly. Cryo-electron tomograms show that tubes span the periplasmic space and are present while the genome is being delivered into the host cell's cytoplasm. Both ends of the H protein contain transmembrane domains, which anchor the assembled tubes into the inner and outer cell membranes. The central channel of the H-protein tube is lined with amide and guanidinium side chains. This may be a general property of viral DNA conduits and is likely to be critical for efficient genome translocation into the host.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Lei -- Young, Lindsey N -- Zhang, Xinzheng -- Boudko, Sergei P -- Fokine, Andrei -- Zbornik, Erica -- Roznowski, Aaron P -- Molineux, Ian J -- Rossmann, Michael G -- Fane, Bentley A -- England -- Nature. 2014 Jan 16;505(7483):432-5. doi: 10.1038/nature12816. Epub 2013 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA [2]. ; 1] School of Plant Sciences and the BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA [2]. ; 1] Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA [2] The Research Department, Shriner's Hospital for Children, Portland, Oregon 97239, USA. ; Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Plant Sciences and the BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA. ; Molecular Genetics and Microbiology, Institute for Cell and Molecular Biology, The 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/24336205" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage phi X 174/*chemistry/*metabolism/ultrastructure ; Biological Transport ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cytoplasm/metabolism/ultrastructure/virology ; DNA, Viral/*metabolism/ultrastructure ; Escherichia coli/cytology/ultrastructure/*virology ; Genome, Viral ; Models, Molecular ; Periplasm/metabolism/ultrastructure ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Viral Proteins/chemistry/metabolism/ultrastructure ; *Virus Assembly
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    Structural basis of the alternating-access mechanism in a bile acid transporter (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-12-10
    Description: Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na(+)-dependent bile acid transporters involved in enterohepatic recirculation, the Na(+)-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBT(NM)) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na(+) and a taurocholic acid. However, the structural changes that bring bile acid and Na(+) across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na(+) and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na(+).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142352/" 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/PMC4142352/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Xiaoming -- Levin, Elena J -- Pan, Yaping -- McCoy, Jason G -- Sharma, Ruchika -- Kloss, Brian -- Bruni, Renato -- Quick, Matthias -- Zhou, Ming -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01DK088057/DK/NIDDK NIH HHS/ -- R01GM098878/GM/NIGMS NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54 GM095315/GM/NIGMS NIH HHS/ -- U54GM087519/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 23;505(7484):569-73. doi: 10.1038/nature12811. Epub 2013 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3]. ; 1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. ; New York Consortium on Membrane Protein Structure, New York, New York 10027, USA. ; 1] Department of Psychiatry and Center for Molecular Recognition, Columbia University, New York, New York 10032, USA [2] New York State Psychiatric Institute, Division of Molecular Therapeutics, New York, New York 10032, USA. ; 1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3] Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24317697" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Bile Acids and Salts/metabolism ; Biological Transport ; Carrier Proteins/*chemistry/*metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Membrane Glycoproteins/*chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Reproducibility of Results ; Rotation ; Sodium/metabolism ; Structure-Activity Relationship ; Yersinia/*chemistry
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    Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-19
    Description: Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral beta-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open beta-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benoit, Roger M -- Frey, Daniel -- Hilbert, Manuel -- Kevenaar, Josta T -- Wieser, Mara M -- Stirnimann, Christian U -- McMillan, David -- Ceska, Tom -- Lebon, Florence -- Jaussi, Rolf -- Steinmetz, Michel O -- Schertler, Gebhard F X -- Hoogenraad, Casper C -- Capitani, Guido -- Kammerer, Richard A -- England -- Nature. 2014 Jan 2;505(7481):108-11. doi: 10.1038/nature12732. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2]. ; 1] Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands [2]. ; Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; UCB Celltech, UCB Pharma, UCB NewMedicines, Slough SL1 4EN, UK. ; UCB Pharma, UCB NewMedicines, B-1420 Braine-L'Alleud, Belgium. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2] Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland. ; Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240280" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Botulinum Toxins, Type A/*chemistry/*metabolism ; Crystallography, X-Ray ; Endocytosis/drug effects ; HEK293 Cells ; Humans ; Membrane Glycoproteins/*chemistry/*metabolism ; Models, Molecular ; Neostriatum/cytology ; Nerve Tissue Proteins/*chemistry/*metabolism ; Neurons/drug effects ; Peptide Fragments/chemistry/pharmacology ; Structure-Activity Relationship
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    The structural mechanism of KCNH-channel regulation by the eag domain (2013)
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    Publication Date: 2013-08-27
    Description: The KCNH voltage-dependent potassium channels (ether-a-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2 A resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910112/" 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/PMC3910112/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haitin, Yoni -- Carlson, Anne E -- Zagotta, William N -- F32 HL095241/HL/NHLBI NIH HHS/ -- R01 EY010329/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 19;501(7467):444-8. doi: 10.1038/nature12487. Epub 2013 Aug 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23975098" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Ether-A-Go-Go Potassium Channels/*chemistry/genetics/*metabolism ; Humans ; Mice ; Models, Molecular ; Nucleotides, Cyclic/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Static Electricity
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    Structure of the human glucagon class B G-protein-coupled receptor (2013)
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    Publication Date: 2013-07-19
    Description: Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 A resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a 'stalk' region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (~12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the seven transmembrane domain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820480/" 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/PMC3820480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siu, Fai Yiu -- He, Min -- de Graaf, Chris -- Han, Gye Won -- Yang, Dehua -- Zhang, Zhiyun -- Zhou, Caihong -- Xu, Qingping -- Wacker, Daniel -- Joseph, Jeremiah S -- Liu, Wei -- Lau, Jesper -- Cherezov, Vadim -- Katritch, Vsevolod -- Wang, Ming-Wei -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50GM073197/GM/NIGMS NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Glucagon/chemistry/metabolism ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Structure, Tertiary ; Receptors, CXCR4/chemistry/classification ; Receptors, Glucagon/*chemistry/*classification/genetics/metabolism
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    Crystal structure of a folate energy-coupling factor transporter from Lactobacillus brevis (2013)
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    Publication Date: 2013-04-16
    Description: ATP-binding cassette (ABC) transporters, composed of importers and exporters, form one of the biggest protein superfamilies that transport a variety of substrates across the membrane, powered by ATP hydrolysis. Most ABC transporters are composed of two transmembrane domains and two cytoplasmic nucleotide-binding domains. Also, importers from prokaryotes usually have extra solute-binding proteins in the periplasm that are responsible for the binding of substrates. Structures of importers have been reported that suggested a two-state model for the transport mechanism. Energy-coupling factor (ECF) transporters belong to a new class of ATP-binding cassette importers. Each ECF transporter comprises an energy-coupling module consisting of a transmembrane T protein (EcfT), two nucleotide-binding proteins (EcfA and EcfA'), and another transmembrane substrate-specific binding S protein (EcfS). Despite the similarities with ABC transporters, ECF transporters have different organizational and functional properties. The lack of solute-binding proteins in ECF transporters differentiates them clearly from the canonical ABC importers. Previously reported structures of the EcfS proteins RibU and ThiT clearly demonstrated the binding site of substrate riboflavin and thiamine, respectively. However, the organization of the four different components and the transport mechanism of ECF transporters remain unknown. Here we present the structure of an intact folate ECF transporter from Lactobacillus brevis at a resolution of 3 A. This structure was captured in an inward-facing, nucleotide-free conformation with no bound substrate. The folate-binding protein FolT is nearly parallel to the membrane and is bound almost entirely by EcfT, which adopts an L shape and connects to EcfA and EcfA' through two coupling helices. Two conserved XRX motifs from the coupling helices of EcfT have a vital role in energy coupling by docking into EcfA-EcfA'. We propose a transport model that involves a substantial conformational change of FolT.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Ke -- Zhang, Minhua -- Zhao, Qin -- Yu, Fang -- Guo, Hui -- Wang, Chengyuan -- He, Fangyuan -- Ding, Jianping -- Zhang, Peng -- England -- Nature. 2013 May 9;497(7448):268-71. doi: 10.1038/nature12046. Epub 2013 Apr 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Plant Molecular Genetics, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Road, Shanghai 200032, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23584589" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Motifs ; Bacterial Proteins/*chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Folic Acid Transporters/*chemistry/metabolism ; Lactobacillus brevis/*chemistry ; Models, Molecular ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Proteolipids/metabolism
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    Structural basis for the inhibition of bacterial multidrug exporters (2013)
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    Publication Date: 2013-07-03
    Description: The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a pi-pi interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakashima, Ryosuke -- Sakurai, Keisuke -- Yamasaki, Seiji -- Hayashi, Katsuhiko -- Nagata, Chikahiro -- Hoshino, Kazuki -- Onodera, Yoshikuni -- Nishino, Kunihiko -- Yamaguchi, Akihito -- England -- Nature. 2013 Aug 1;500(7460):102-6. doi: 10.1038/nature12300. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812586" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/chemistry/metabolism/pharmacology ; Bacterial Outer Membrane Proteins/antagonists & inhibitors/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/antagonists & inhibitors/*chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Membrane Transport Proteins/*chemistry/metabolism ; Models, Molecular ; Multidrug Resistance-Associated Proteins/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Multimerization ; Pseudomonas aeruginosa/*chemistry/*metabolism ; Pyridines/chemistry/metabolism/pharmacology ; Pyrimidines/chemistry/metabolism/pharmacology ; Pyrimidinones/chemistry/metabolism/pharmacology ; Rotation
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    Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody (2013)
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    Publication Date: 2013-09-24
    Description: G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far, it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists or receptor stabilization by mutagenesis. Many natural agonists such as adrenaline, which activates the beta2-adrenoceptor (beta2AR), bind with relatively low affinity, and they are often chemically unstable. Using directed evolution, we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the beta2AR, and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active-state human beta2AR bound to three chemically distinct agonists: the ultrahigh-affinity agonist BI167107, the high-affinity catecholamine agonist hydroxybenzyl isoproterenol, and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100 nM to approximately 80 pM. Overall, the adrenaline-bound receptor structure is similar to the others, but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines, which appears to stabilize the active state of the beta2AR and related GPCRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822040/" 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/PMC3822040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ring, Aaron M -- Manglik, Aashish -- Kruse, Andrew C -- Enos, Michael D -- Weis, William I -- Garcia, K Christopher -- Kobilka, Brian K -- GM08311806/GM/NIGMS NIH HHS/ -- NS02847123/NS/NINDS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471/NS/NINDS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Oct 24;502(7472):575-9. doi: 10.1038/nature12572. Epub 2013 Sep 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA [2] Department of Structural Biology, Stanford University, Stanford, California 94305, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24056936" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor Agonists/*pharmacology ; Benzoxazines/pharmacology ; Binding Sites/drug effects ; Crystallography, X-Ray ; Directed Molecular Evolution ; Epinephrine/*pharmacology ; Humans ; Hydrogen Bonding/drug effects ; Isoproterenol/analogs & derivatives/pharmacology ; Ligands ; Models, Molecular ; *Protein Engineering ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-2/*chemistry/drug effects/*metabolism ; Single-Chain Antibodies/genetics/*pharmacology ; Tyrosine/chemistry/metabolism ; Water/chemistry/pharmacology
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    RNA polymerase I structure and transcription regulation (2013)
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    Publication Date: 2013-10-25
    Description: Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of Pol I from the yeast Saccharomyces cerevisiae at 2.8 A resolution reveals all 14 subunits of the 590-kilodalton enzyme, and shows differences to Pol II. An 'expander' element occupies the DNA template site and stabilizes an expanded active centre cleft with an unwound bridge helix. A 'connector' element invades the cleft of an adjacent polymerase and stabilizes an inactive polymerase dimer. The connector and expander must detach during Pol I activation to enable transcription initiation and cleft contraction by convergent movement of the polymerase 'core' and 'shelf' modules. Conversion between an inactive expanded and an active contracted polymerase state may generally underlie transcription. Regulatory factors can modulate the core-shelf interface that includes a 'composite' active site for RNA chain initiation, elongation, proofreading and termination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Engel, Christoph -- Sainsbury, Sarah -- Cheung, Alan C -- Kostrewa, Dirk -- Cramer, Patrick -- England -- Nature. 2013 Oct 31;502(7473):650-5. doi: 10.1038/nature12712. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Department of Biochemistry, Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Str. 25, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153182" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; *Gene Expression Regulation ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; RNA Polymerase I/*chemistry/*metabolism ; Saccharomyces cerevisiae/*enzymology ; Transcription Factors, TFII/chemistry/metabolism ; *Transcription, Genetic
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    Structural basis of kynurenine 3-monooxygenase inhibition (2013)
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    Publication Date: 2013-04-12
    Description: Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736096/" 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/PMC3736096/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amaral, Marta -- Levy, Colin -- Heyes, Derren J -- Lafite, Pierre -- Outeiro, Tiago F -- Giorgini, Flaviano -- Leys, David -- Scrutton, Nigel S -- BB/D01963X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2013 Apr 18;496(7445):382-5. doi: 10.1038/nature12039. Epub 2013 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Manchester Institute of Biotechnology, The 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/23575632" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/metabolism ; Blood-Brain Barrier/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Cyclopropanes/*chemistry/*pharmacology ; Drug Design ; Enzyme Inhibitors/*chemistry/*pharmacology ; Humans ; Huntington Disease/drug therapy/enzymology ; Kynurenine/metabolism ; Kynurenine 3-Monooxygenase/*antagonists & inhibitors/*chemistry/metabolism ; Models, Molecular ; Molecular Targeted Therapy ; Protein Conformation ; Reproducibility of Results ; Saccharomyces cerevisiae/*enzymology ; Structure-Activity Relationship
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    The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis (2013)
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    Publication Date: 2013-05-28
    Description: A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-kappaB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivkin, Elena -- Almeida, Stephanie M -- Ceccarelli, Derek F -- Juang, Yu-Chi -- MacLean, Teresa A -- Srikumar, Tharan -- Huang, Hao -- Dunham, Wade H -- Fukumura, Ryutaro -- Xie, Gang -- Gondo, Yoichi -- Raught, Brian -- Gingras, Anne-Claude -- Sicheri, Frank -- Cordes, Sabine P -- IHO 94384/Canadian Institutes of Health Research/Canada -- MOP 111199/Canadian Institutes of Health Research/Canada -- MOP 97966/Canadian Institutes of Health Research/Canada -- MOP119289/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708998" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Crystallography, X-Ray ; Embryo, Mammalian/blood supply/embryology/metabolism ; Endopeptidases/*chemistry/deficiency/genetics/*metabolism ; Female ; Gene Expression Profiling ; HEK293 Cells ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; *Neovascularization, Physiologic/genetics ; Phenotype ; Phosphoproteins/metabolism ; Protein Conformation ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; *Ubiquitination ; Wnt Signaling Pathway
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    Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement (2013)
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    Publication Date: 2013-10-29
    Description: Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(beta-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844076/" 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/PMC3844076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teufel, Robin -- Miyanaga, Akimasa -- Michaudel, Quentin -- Stull, Frederick -- Louie, Gordon -- Noel, Joseph P -- Baran, Phil S -- Palfey, Bruce -- Moore, Bradley S -- R01 AI047818/AI/NIAID NIH HHS/ -- R01AI47818/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):552-6. doi: 10.1038/nature12643. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162851" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/biosynthesis ; Bacterial Proteins/chemistry/*metabolism ; Biocatalysis ; Bridged Compounds/metabolism ; Crystallography, X-Ray ; Cyclization ; Flavins/*metabolism ; Flavoproteins/chemistry/*metabolism ; Isotope Labeling ; Mixed Function Oxygenases/chemistry/*metabolism ; Models, Chemical ; Models, Molecular ; Oxidation-Reduction ; Polyketides/metabolism ; Protein Conformation ; Streptomyces/*enzymology/metabolism ; Substrate Specificity
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    mTOR kinase structure, mechanism and regulation (2013)
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    Publication Date: 2013-05-03
    Description: The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754/" 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/PMC4512754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Haijuan -- Rudge, Derek G -- Koos, Joseph D -- Vaidialingam, Bhamini -- Yang, Hyo J -- Pavletich, Nikola P -- P30 CA008748/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 9;497(7448):217-23. doi: 10.1038/nature12122. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636326" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/metabolism ; Adenosine Triphosphate/chemistry/metabolism ; Catalytic Domain/drug effects ; Crystallography, X-Ray ; Furans/chemistry/pharmacology ; Humans ; Indoles/chemistry/metabolism/pharmacology ; Magnesium/chemistry/metabolism ; Models, Molecular ; Naphthyridines/chemistry/metabolism/pharmacology ; Protein Structure, Tertiary/drug effects ; Purines/chemistry/metabolism/pharmacology ; Pyridines/chemistry/pharmacology ; Pyrimidines/chemistry/pharmacology ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sirolimus/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism ; Tacrolimus Binding Protein 1A/chemistry/metabolism/pharmacology
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    Recovery from slow inactivation in K+ channels is controlled by water molecules (2013)
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    Publication Date: 2013-07-31
    Description: Application of a specific stimulus opens the intracellular gate of a K(+) channel (activation), yielding a transient period of ion conduction until the selectivity filter spontaneously undergoes a conformational change towards a non-conductive state (inactivation). Removal of the stimulus closes the gate and allows the selectivity filter to interconvert back to its conductive conformation (recovery). Given that the structural differences between the conductive and inactivated filter are very small, it is unclear why the recovery process can take up to several seconds. The bacterial K(+) channel KcsA from Streptomyces lividans can be used to help elucidate questions about channel inactivation and recovery at the atomic level. Although KcsA contains only a pore domain, without voltage-sensing machinery, it has the structural elements necessary for ion conduction, activation and inactivation. Here we reveal, by means of a series of long molecular dynamics simulations, how the selectivity filter is sterically locked in the inactive conformation by buried water molecules bound behind the selectivity filter. Potential of mean force calculations show how the recovery process is affected by the buried water molecules and the rebinding of an external K(+) ion. A kinetic model deduced from the simulations shows how releasing the buried water molecules can stretch the timescale of recovery to seconds. This leads to the prediction that reducing the occupancy of the buried water molecules by imposing a high osmotic stress should accelerate the rate of recovery, which was verified experimentally by measuring the recovery rate in the presence of a 2-molar sucrose concentration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799803/" 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/PMC3799803/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ostmeyer, Jared -- Chakrapani, Sudha -- Pan, Albert C -- Perozo, Eduardo -- Roux, Benoit -- R01 GM057846/GM/NIGMS NIH HHS/ -- R01 GM062342/GM/NIGMS NIH HHS/ -- R01-GM062342/GM/NIGMS NIH HHS/ -- R01-GM57846/GM/NIGMS NIH HHS/ -- RC2GM093307/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Sep 5;501(7465):121-4. doi: 10.1038/nature12395. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, 929 E57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892782" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallization ; Crystallography, X-Ray ; Ion Channel Gating/*drug effects ; Kinetics ; *Molecular Dynamics Simulation ; Potassium/metabolism ; Potassium Channels/*chemistry/*metabolism ; Protein Conformation ; Streptomyces lividans/chemistry ; Sucrose/pharmacology ; Thermodynamics ; Water/chemistry/metabolism/*pharmacology
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    Control of substrate access to the active site in methane monooxygenase (2013)
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    Publication Date: 2013-02-12
    Description: Methanotrophs consume methane as their major carbon source and have an essential role in the global carbon cycle by limiting escape of this greenhouse gas to the atmosphere. These bacteria oxidize methane to methanol by soluble and particulate methane monooxygenases (MMOs). Soluble MMO contains three protein components, a 251-kilodalton hydroxylase (MMOH), a 38.6-kilodalton reductase (MMOR), and a 15.9-kilodalton regulatory protein (MMOB), required to couple electron consumption with substrate hydroxylation at the catalytic diiron centre of MMOH. Until now, the role of MMOB has remained ambiguous owing to a lack of atomic-level information about the MMOH-MMOB (hereafter termed H-B) complex. Here we remedy this deficiency by providing a crystal structure of H-B, which reveals the manner by which MMOB controls the conformation of residues in MMOH crucial for substrate access to the active site. MMOB docks at the alpha(2)beta(2) interface of alpha(2)beta(2)gamma(2) MMOH, and triggers simultaneous conformational changes in the alpha-subunit that modulate oxygen and methane access as well as proton delivery to the diiron centre. Without such careful control by MMOB of these substrate routes to the diiron active site, the enzyme operates as an NADH oxidase rather than a monooxygenase. Biological catalysis involving small substrates is often accomplished in nature by large proteins and protein complexes. The structure presented in this work provides an elegant example of this principle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596810/" 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/PMC3596810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Seung Jae -- McCormick, Michael S -- Lippard, Stephen J -- Cho, Uhn-Soo -- GM 32114/GM/NIGMS NIH HHS/ -- R01 GM032134/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):380-4. doi: 10.1038/nature11880. Epub 2013 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23395959" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Iron/metabolism ; Methylococcus capsulatus/*enzymology ; Mixed Function Oxygenases/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/*chemistry/*metabolism ; Oxidoreductases/chemistry/metabolism ; Oxygenases/*chemistry/*metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-05
    Description: Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637846/" 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/PMC3637846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liao, Hua-Xin -- Lynch, Rebecca -- Zhou, Tongqing -- Gao, Feng -- Alam, S Munir -- Boyd, Scott D -- Fire, Andrew Z -- Roskin, Krishna M -- Schramm, Chaim A -- Zhang, Zhenhai -- Zhu, Jiang -- Shapiro, Lawrence -- NISC Comparative Sequencing Program -- Mullikin, James C -- Gnanakaran, S -- Hraber, Peter -- Wiehe, Kevin -- Kelsoe, Garnett -- Yang, Guang -- Xia, Shi-Mao -- Montefiori, David C -- Parks, Robert -- Lloyd, Krissey E -- Scearce, Richard M -- Soderberg, Kelly A -- Cohen, Myron -- Kamanga, Gift -- Louder, Mark K -- Tran, Lillian M -- Chen, Yue -- Cai, Fangping -- Chen, Sheri -- Moquin, Stephanie -- Du, Xiulian -- Joyce, M Gordon -- Srivatsan, Sanjay -- Zhang, Baoshan -- Zheng, Anqi -- Shaw, George M -- Hahn, Beatrice H -- Kepler, Thomas B -- Korber, Bette T M -- Kwong, Peter D -- Mascola, John R -- Haynes, Barton F -- AI067854/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):469-76. doi: 10.1038/nature12053. Epub 2013 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke University Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, North Carolina 27710, USA. hliao@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552890" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Africa ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/genetics/immunology ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antigens, CD4/chemistry/immunology ; Cell Lineage ; Cells, Cultured ; Clone Cells/cytology ; Cross Reactions/immunology ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; *Evolution, Molecular ; HIV Antibodies/*chemistry/genetics/*immunology ; HIV Envelope Protein gp120/chemistry/genetics/immunology/metabolism ; HIV-1/*chemistry/classification/*immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neutralization Tests ; Phylogeny ; Protein Structure, Tertiary
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    Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state (2013)
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    Publication Date: 2013-03-05
    Description: P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across biological membranes, and are distinct from other ATPases in that the reaction cycle includes an autophosphorylation step. The best studied is Ca(2+)-ATPase from muscle sarcoplasmic reticulum (SERCA1a), a Ca(2+) pump that relaxes muscle cells after contraction, and crystal structures have been determined for most of the reaction intermediates. An important outstanding structure is that of the E1 intermediate, which has empty high-affinity Ca(2+)-binding sites ready to accept new cytosolic Ca(2+). In the absence of Ca(2+) and at pH 7 or higher, the ATPase is predominantly in E1, not in E2 (low affinity for Ca(2+)), and if millimolar Mg(2+) is present, one Mg(2+) is expected to occupy one of the Ca(2+)-binding sites with a millimolar dissociation constant. This Mg(2+) accelerates the reaction cycle, not permitting phosphorylation without Ca(2+) binding. Here we describe the crystal structure of native SERCA1a (from rabbit) in this E1.Mg(2+) state at 3.0 A resolution in addition to crystal structures of SERCA1a in E2 free from exogenous inhibitors, and address the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca(2+)-ATPase, is bound, stabilizing the E1.Mg(2+) state. Sarcolipin is a close homologue of phospholamban, which is a critical mediator of beta-adrenergic signal in Ca(2+) regulation in heart (for reviews, see, for example, refs 8-10), and seems to play an important role in muscle-based thermogenesis. We also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and describe the structural basis of inhibition by sarcolipin/phospholamban. Thus, the crystal structures reported here fill a gap in the structural elucidation of the reaction cycle and provide a solid basis for understanding the physiological regulation of the calcium pump.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toyoshima, Chikashi -- Iwasawa, Shiho -- Ogawa, Haruo -- Hirata, Ayami -- Tsueda, Junko -- Inesi, Giuseppe -- England -- Nature. 2013 Mar 14;495(7440):260-4. doi: 10.1038/nature11899. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. ct@iam.u-tokyo.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455422" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/drug effects ; Calcium-Binding Proteins/pharmacology ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Magnesium/chemistry/*metabolism/pharmacology ; Models, Molecular ; Muscle Proteins/*chemistry/*metabolism/pharmacology ; Phosphorylation ; Protein Binding ; Protein Conformation/drug effects ; Proteolipids/*chemistry/*metabolism/pharmacology ; Rabbits ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & ; inhibitors/*chemistry/*metabolism
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    Crystal structure of a eukaryotic phosphate transporter (2013)
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    Publication Date: 2013-04-02
    Description: Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 A structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical 'rocker-switch' mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678552/" 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/PMC3678552/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pedersen, Bjorn P -- Kumar, Hemant -- Waight, Andrew B -- Risenmay, Aaron J -- Roe-Zurz, Zygy -- Chau, Bryant H -- Schlessinger, Avner -- Bonomi, Massimiliano -- Harries, William -- Sali, Andrej -- Johri, Atul K -- Stroud, Robert M -- F32 GM088991/GM/NIGMS NIH HHS/ -- GM073210/GM/NIGMS NIH HHS/ -- GM24485/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 GM024485/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- U01 GM61390/GM/NIGMS NIH HHS/ -- U19 GM061390/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):533-6. doi: 10.1038/nature12042. Epub 2013 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23542591" target="_blank"〉PubMed〈/a〉
    Keywords: Basidiomycota/*chemistry ; Binding Sites ; Crystallography, X-Ray ; Eukaryotic Cells/*chemistry ; Humans ; Models, Biological ; Models, Molecular ; Phosphate Transport Proteins/*chemistry/metabolism ; Phosphates/metabolism ; Protein Conformation ; Protons ; Structure-Activity Relationship
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    Crystal structure of an RNA-bound 11-subunit eukaryotic exosome complex (2013)
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    Publication Date: 2013-02-05
    Description: The exosome is the major 3'-5' RNA-degradation complex in eukaryotes. The ubiquitous core of the yeast exosome (Exo-10) is formed by nine catalytically inert subunits (Exo-9) and a single active RNase, Rrp44. In the nucleus, the Exo-10 core recruits another nuclease, Rrp6. Here we crystallized an approximately 440-kilodalton complex of Saccharomyces cerevisiae Exo-10 bound to a carboxy-terminal region of Rrp6 and to an RNA duplex with a 3'-overhang of 31 ribonucleotides. The 2.8 A resolution structure shows how RNA is funnelled into the Exo-9 channel in a single-stranded conformation by an unwinding pore. Rrp44 adopts a closed conformation and captures the RNA 3'-end that exits from the side of Exo-9. Exo-9 subunits bind RNA with sequence-unspecific interactions reminiscent of archaeal exosomes. The substrate binding and channelling mechanisms of 3'-5' RNA degradation complexes are conserved in all kingdoms of life.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makino, Debora Lika -- Baumgartner, Marc -- Conti, Elena -- England -- Nature. 2013 Mar 7;495(7439):70-5. doi: 10.1038/nature11870. Epub 2013 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Cell Biology, MPI for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23376952" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Exosome Multienzyme Ribonuclease Complex/*chemistry/*metabolism ; Models, Molecular ; Protein Subunits/*chemistry/metabolism ; RNA/chemistry/*metabolism ; Saccharomyces cerevisiae/*chemistry/genetics ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism
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    Computational design of ligand-binding proteins with high affinity and selectivity (2013)
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    Publication Date: 2013-09-06
    Description: The ability to design proteins with high affinity and selectivity for any given small molecule is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition. Attempts to rationally design ligand-binding proteins have met with little success, however, and the computational design of protein-small-molecule interfaces remains an unsolved problem. Current approaches for designing ligand-binding proteins for medical and biotechnological uses rely on raising antibodies against a target antigen in immunized animals and/or performing laboratory-directed evolution of proteins with an existing low affinity for the desired ligand, neither of which allows complete control over the interactions involved in binding. Here we describe a general computational method for designing pre-organized and shape complementary small-molecule-binding sites, and use it to generate protein binders to the steroid digoxigenin (DIG). Of seventeen experimentally characterized designs, two bind DIG; the model of the higher affinity binder has the most energetically favourable and pre-organized interface in the design set. A comprehensive binding-fitness landscape of this design, generated by library selections and deep sequencing, was used to optimize its binding affinity to a picomolar level, and X-ray co-crystal structures of two variants show atomic-level agreement with the corresponding computational models. The optimized binder is selective for DIG over the related steroids digitoxigenin, progesterone and beta-oestradiol, and this steroid binding preference can be reprogrammed by manipulation of explicitly designed hydrogen-bonding interactions. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898436/" 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/PMC3898436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tinberg, Christine E -- Khare, Sagar D -- Dou, Jiayi -- Doyle, Lindsey -- Nelson, Jorgen W -- Schena, Alberto -- Jankowski, Wojciech -- Kalodimos, Charalampos G -- Johnsson, Kai -- Stoddard, Barry L -- Baker, David -- P41 GM103533/GM/NIGMS NIH HHS/ -- R01 GM049857/GM/NIGMS NIH HHS/ -- T32 HG000035/HG/NHGRI NIH HHS/ -- T32 HG00035/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Sep 12;501(7466):212-6. doi: 10.1038/nature12443. Epub 2013 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24005320" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biotechnology ; *Computer Simulation ; Crystallography, X-Ray ; Digoxigenin/chemistry/*metabolism ; *Drug Design ; Estradiol/chemistry/metabolism ; Ligands ; Models, Molecular ; Progesterone/chemistry/metabolism ; Protein Binding ; Proteins/*chemistry/*metabolism ; Reproducibility of Results ; Substrate Specificity
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    Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1 (2013)
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    Publication Date: 2013-12-03
    Description: CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis. The approximately 120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamily of small GTPases, nuclear lamins, the gamma-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases. The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum. Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane alpha-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located approximately 10 A into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane alpha-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864837/" 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/PMC3864837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manolaridis, Ioannis -- Kulkarni, Kiran -- Dodd, Roger B -- Ogasawara, Satoshi -- Zhang, Ziguo -- Bineva, Ganka -- O'Reilly, Nicola -- Hanrahan, Sarah J -- Thompson, Andrew J -- Cronin, Nora -- Iwata, So -- Barford, David -- 100140/Wellcome Trust/United Kingdom -- A2560/Cancer Research UK/United Kingdom -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):301-5. doi: 10.1038/nature12754. Epub 2013 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] [3] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Department of Life Sciences, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24291792" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Archaeal Proteins/chemistry/metabolism ; *Biocatalysis ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Endopeptidases/chemistry/metabolism ; Endoplasmic Reticulum/enzymology ; Escherichia coli Proteins/chemistry/metabolism ; Glutamic Acid/metabolism ; Humans ; Membrane Proteins/*chemistry/metabolism ; Metalloendopeptidases/chemistry/metabolism ; Methanococcus/*enzymology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Peptide Hydrolases/*chemistry/classification/*metabolism ; *Prenylation ; Protein Structure, Tertiary ; Proto-Oncogene Proteins p21(ras)/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity
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    Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide (2013)
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    Publication Date: 2013-04-23
    Description: The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of beta-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of beta-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate beta-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654799/" 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/PMC3654799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Arun K -- Manglik, Aashish -- Kruse, Andrew C -- Xiao, Kunhong -- Reis, Rosana I -- Tseng, Wei-Chou -- Staus, Dean P -- Hilger, Daniel -- Uysal, Serdar -- Huang, Li-Yin -- Paduch, Marcin -- Tripathi-Shukla, Prachi -- Koide, Akiko -- Koide, Shohei -- Weis, William I -- Kossiakoff, Anthony A -- Kobilka, Brian K -- Lefkowitz, Robert J -- GM072688/GM/NIGMS NIH HHS/ -- GM087519/GM/NIGMS NIH HHS/ -- HL 075443/HL/NHLBI NIH HHS/ -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM074946/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 2;497(7447):137-41. doi: 10.1038/nature12120. Epub 2013 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23604254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestins/*chemistry/immunology/*metabolism ; Crystallography, X-Ray ; Humans ; Immunoglobulin Fab Fragments/chemistry/immunology/metabolism ; Models, Molecular ; Phosphopeptides/*chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Conformation ; Protein Stability ; Rats ; Receptors, Vasopressin/*chemistry ; Rotation
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    Structure of a bacterial energy-coupling factor transporter (2013)
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    Publication Date: 2013-04-16
    Description: The energy-coupling factor (ECF) transporters constitute a novel family of conserved membrane transporters in prokaryotes that have a similar domain organization to the ATP-binding cassette transporters. Each ECF transporter comprises a pair of cytosolic ATPases (the A and A' components, or EcfA and EcfA'), a membrane-embedded substrate-binding protein (the S component, or EcfS) and a transmembrane energy-coupling component (the T component, or EcfT) that links the EcfA-EcfA' subcomplex to EcfS. The structure and transport mechanism of the quaternary ECF transporter remain largely unknown. Here we report the crystal structure of a nucleotide-free ECF transporter from Lactobacillus brevis at a resolution of 3.5 A. The T component has a horseshoe-shaped open architecture, with five alpha-helices as transmembrane segments and two cytoplasmic alpha-helices as coupling modules connecting to the A and A' components. Strikingly, the S component, thought to be specific for hydroxymethyl pyrimidine, lies horizontally along the lipid membrane and is bound exclusively by the five transmembrane segments and the two cytoplasmic helices of the T component. These structural features suggest a plausible working model for the transport cycle of the ECF transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Tingliang -- Fu, Guobin -- Pan, Xiaojing -- Wu, Jianping -- Gong, Xinqi -- Wang, Jiawei -- Shi, Yigong -- England -- Nature. 2013 May 9;497(7448):272-6. doi: 10.1038/nature12045. Epub 2013 Apr 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23584587" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Anti-Bacterial Agents ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Cytoplasm/chemistry/metabolism ; Lactobacillus brevis/*chemistry ; Models, Biological ; Models, Molecular ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Pyrimidines/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state (2013)
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    Publication Date: 2013-10-04
    Description: Na(+),K(+)-ATPase pumps three Na(+) ions out of cells in exchange for two K(+) taken up from the extracellular medium per ATP molecule hydrolysed, thereby establishing Na(+) and K(+) gradients across the membrane in all animal cells. These ion gradients are used in many fundamental processes, notably excitation of nerve cells. Here we describe 2.8 A-resolution crystal structures of this ATPase from pig kidney with bound Na(+), ADP and aluminium fluoride, a stable phosphate analogue, with and without oligomycin that promotes Na(+) occlusion. These crystal structures represent a transition state preceding the phosphorylated intermediate (E1P) in which three Na(+) ions are occluded. Details of the Na(+)-binding sites show how this ATPase functions as a Na(+)-specific pump, rejecting K(+) and Ca(2+), even though its affinity for Na(+) is low (millimolar dissociation constant). A mechanism for sequential, cooperative Na(+) binding can now be formulated in atomic detail.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanai, Ryuta -- Ogawa, Haruo -- Vilsen, Bente -- Cornelius, Flemming -- Toyoshima, Chikashi -- England -- Nature. 2013 Oct 10;502(7470):201-6. doi: 10.1038/nature12578. Epub 2013 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24089211" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Kidney/enzymology ; *Models, Molecular ; Protein Structure, Tertiary ; Sodium/*chemistry ; Sodium-Potassium-Exchanging ATPase/*chemistry ; Swine
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    How insulin engages its primary binding site on the insulin receptor (2013)
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    Publication Date: 2013-01-11
    Description: Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alphaCT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793637/" 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/PMC3793637/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Menting, John G -- Whittaker, Jonathan -- Margetts, Mai B -- Whittaker, Linda J -- Kong, Geoffrey K-W -- Smith, Brian J -- Watson, Christopher J -- Zakova, Lenka -- Kletvikova, Emilia -- Jiracek, Jiri -- Chan, Shu Jin -- Steiner, Donald F -- Dodson, Guy G -- Brzozowski, Andrzej M -- Weiss, Michael A -- Ward, Colin W -- Lawrence, Michael C -- DK13914/DK/NIDDK NIH HHS/ -- DK20595/DK/NIDDK NIH HHS/ -- DK40949/DK/NIDDK NIH HHS/ -- R01 DK040949/DK/NIDDK NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2013 Jan 10;493(7431):241-5. doi: 10.1038/nature11781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23302862" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calorimetry ; Cattle ; Cell Line ; Crystallography, X-Ray ; Humans ; Insulin/*chemistry/*metabolism ; Leucine/metabolism ; Ligands ; Models, Molecular ; Protein Binding ; Protein Structure, Secondary ; Receptor, Insulin/*chemistry/*metabolism ; Reproducibility of Results
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    The structure of the KtrAB potassium transporter (2013)
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    Publication Date: 2013-04-20
    Description: In bacteria, archaea, fungi and plants the Trk, Ktr and HKT ion transporters are key components of osmotic regulation, pH homeostasis and resistance to drought and high salinity. These ion transporters are functionally diverse: they can function as Na(+) or K(+) channels and possibly as cation/K(+) symporters. They are closely related to potassium channels both at the level of the membrane protein and at the level of the cytosolic regulatory domains. Here we describe the crystal structure of a Ktr K(+) transporter, the KtrAB complex from Bacillus subtilis. The structure shows the dimeric membrane protein KtrB assembled with a cytosolic octameric KtrA ring bound to ATP, an activating ligand. A comparison between the structure of KtrAB-ATP and the structures of the isolated full-length KtrA protein with ATP or ADP reveals a ligand-dependent conformational change in the octameric ring, raising new ideas about the mechanism of activation in these transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vieira-Pires, Ricardo S -- Szollosi, Andras -- Morais-Cabral, Joao H -- England -- Nature. 2013 Apr 18;496(7445):323-8. doi: 10.1038/nature12055.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, Porto 4150-180, Portugal.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598340" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Bacillus subtilis/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Cation Transport Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Ion Transport ; Models, Biological ; Models, Molecular ; Potassium/*metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship
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    Vinylogous chain branching catalysed by a dedicated polyketide synthase module (2013)
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    Publication Date: 2013-09-21
    Description: Bacteria use modular polyketide synthases (PKSs) to assemble complex polyketides, many of which are leads for the development of clinical drugs, in particular anti-infectives and anti-tumoral agents. Because these multifarious compounds are notoriously difficult to synthesize, they are usually produced by microbial fermentation. During the past two decades, an impressive body of knowledge on modular PKSs has been gathered that not only provides detailed insight into the biosynthetic pathways but also allows the rational engineering of enzymatic processing lines to yield structural analogues. Notably, a hallmark of all PKS modules studied so far is the head-to-tail fusion of acyl and malonyl building blocks, which leads to linear backbones. Yet, structural diversity is limited by this uniform assembly mode. Here we demonstrate a new type of PKS module from the endofungal bacterium Burkholderia rhizoxinica that catalyses a Michael-type acetyl addition to generate a branch in the carbon chain. In vitro reconstitution of the entire PKS module, X-ray structures of a ketosynthase-branching didomain and mutagenesis experiments revealed a crucial role of the ketosynthase domain in branching the carbon chain. We present a trapped intermediary state in which acyl carrier protein and ketosynthase are covalently linked by the branched polyketide and suggest a new mechanism for chain alkylation, which is functionally distinct from terpenoid-like beta-branching. For the rice seedling blight toxin rhizoxin, one of the strongest known anti-mitotic agents, the non-canonical polyketide modification is indispensable for phytotoxic and anti-tumoral activities. We propose that the formation of related pharmacophoric groups follows the same general scheme and infer a unifying vinylogous branching reaction for PKS modules with a ketosynthase-branching-acyl-carrier-protein architecture. This study unveils the structure and function of a new PKS module that broadens the biosynthetic scope of polyketide biosynthesis and sets the stage for rationally creating structural diversity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bretschneider, Tom -- Heim, Joel B -- Heine, Daniel -- Winkler, Robert -- Busch, Benjamin -- Kusebauch, Bjorn -- Stehle, Thilo -- Zocher, Georg -- Hertweck, Christian -- England -- Nature. 2013 Oct 3;502(7469):124-8. doi: 10.1038/nature12588. Epub 2013 Sep 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena 07745, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24048471" target="_blank"〉PubMed〈/a〉
    Keywords: Burkholderia/chemistry/*enzymology/genetics ; Catalysis ; Crystallography, X-Ray ; Lactones/metabolism ; Macrolides/chemistry ; *Models, Molecular ; Mutagenesis ; Polyketide Synthases/genetics/*metabolism ; Protein Structure, Tertiary
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    Q&A: The technology starter. Interview by Valerie Gerard (2013)
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    Publication Date: 2013-10-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shechtman, Dan -- England -- Nature. 2013 Oct 17;502(7471):S54-5. doi: 10.1038/502S54a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24132333" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; Developing Countries ; Education/statistics & numerical data ; Entrepreneurship/*economics ; Leadership ; Nobel Prize ; Research ; Technology/*economics
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    Structural basis for alternating access of a eukaryotic calcium/proton exchanger (2013)
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    Publication Date: 2013-05-21
    Description: Eukaryotic Ca(2+) regulation involves sequestration into intracellular organelles, and expeditious Ca(2+) release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca(2+) after such signalling events is accomplished by members of the Ca(2+):cation (CaCA) superfamily. The CaCA superfamily includes the Na(+)/Ca(2+) (NCX) and Ca(2+)/H(+) (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are responsible for the re-establishment of Ca(2+) resting potential in muscle cells, neuronal signalling and Ca(2+) reabsorption in the kidney. The CAX family members maintain cytosolic Ca(2+) homeostasis in plants and fungi during steep rises in intracellular Ca(2+) due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca(2+)/H(+) exchanger (Vcx1) at 2.3 A resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the CaCA superfamily performs high-throughput Ca(2+) transport across membranes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702627/" 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/PMC3702627/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waight, Andrew B -- Pedersen, Bjorn Panyella -- Schlessinger, Avner -- Bonomi, Massimiliano -- Chau, Bryant H -- Roe-Zurz, Zygy -- Risenmay, Aaron J -- Sali, Andrej -- Stroud, Robert M -- GM073210/GM/NIGMS NIH HHS/ -- GM24485/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 GM024485/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- U01 GM61390/GM/NIGMS NIH HHS/ -- U19 GM061390/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 4;499(7456):107-10. doi: 10.1038/nature12233. Epub 2013 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23685453" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antiporters/*chemistry/*metabolism ; Binding Sites ; Calcium/*metabolism ; Crystallography, X-Ray ; Cytosol/*metabolism ; Ion Transport ; Methanococcus/chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Folding ; *Protons ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Structure-Activity Relationship
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    Trapping the dynamic acyl carrier protein in fatty acid biosynthesis (2013)
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    Publication Date: 2013-12-24
    Description: Acyl carrier protein (ACP) transports the growing fatty acid chain between enzymatic domains of fatty acid synthase (FAS) during biosynthesis. Because FAS enzymes operate on ACP-bound acyl groups, ACP must stabilize and transport the growing lipid chain. ACPs have a central role in transporting starting materials and intermediates throughout the fatty acid biosynthetic pathway. The transient nature of ACP-enzyme interactions impose major obstacles to obtaining high-resolution structural information about fatty acid biosynthesis, and a new strategy is required to study protein-protein interactions effectively. Here we describe the application of a mechanism-based probe that allows active site-selective covalent crosslinking of AcpP to FabA, the Escherichia coli ACP and fatty acid 3-hydroxyacyl-ACP dehydratase, respectively. We report the 1.9 A crystal structure of the crosslinked AcpP-FabA complex as a homodimer in which AcpP exhibits two different conformations, representing probable snapshots of ACP in action: the 4'-phosphopantetheine group of AcpP first binds an arginine-rich groove of FabA, then an AcpP helical conformational change locks AcpP and FabA in place. Residues at the interface of AcpP and FabA are identified and validated by solution nuclear magnetic resonance techniques, including chemical shift perturbations and residual dipolar coupling measurements. These not only support our interpretation of the crystal structures but also provide an animated view of ACP in action during fatty acid dehydration. These techniques, in combination with molecular dynamics simulations, show for the first time that FabA extrudes the sequestered acyl chain from the ACP binding pocket before dehydration by repositioning helix III. Extensive sequence conservation among carrier proteins suggests that the mechanistic insights gleaned from our studies may be broadly applicable to fatty acid, polyketide and non-ribosomal biosynthesis. Here the foundation is laid for defining the dynamic action of carrier-protein activity in primary and secondary metabolism, providing insight into pathways that can have major roles in the treatment of cancer, obesity and infectious disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437705/" 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/PMC4437705/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nguyen, Chi -- Haushalter, Robert W -- Lee, D John -- Markwick, Phineus R L -- Bruegger, Joel -- Caldara-Festin, Grace -- Finzel, Kara -- Jackson, David R -- Ishikawa, Fumihiro -- O'Dowd, Bing -- McCammon, J Andrew -- Opella, Stanley J -- Tsai, Shiou-Chuan -- Burkart, Michael D -- GM095970/GM/NIGMS NIH HHS/ -- GM100305/GM/NIGMS NIH HHS/ -- P41 EB002031/EB/NIBIB NIH HHS/ -- R01 GM066978/GM/NIGMS NIH HHS/ -- R01 GM095970/GM/NIGMS NIH HHS/ -- R01 GM100305/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 16;505(7483):427-31. doi: 10.1038/nature12810. Epub 2013 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical Sciences, University of California, Irvine, California 92697, USA [2]. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2]. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] San Diego Supercomputer Center, La Jolla, California 92093, USA [3] Howard Hughes Medical Institute, La Jolla, California 92093, USA. ; Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical Sciences, University of California, Irvine, California 92697, USA. ; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] Howard Hughes Medical Institute, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24362570" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Carrier Protein/*chemistry/*metabolism ; Binding Sites ; Catalytic Domain ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Fatty Acid Synthase, Type II/chemistry/metabolism ; Fatty Acids/*biosynthesis ; Histidine/metabolism ; Hydro-Lyases/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Binding ; Protein Interaction Maps
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    Antibacterial membrane attack by a pore-forming intestinal C-type lectin (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-22
    Description: Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIalpha (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIalpha pore by docking the RegIIIalpha crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIalpha pore-forming activity, explaining why RegIIIalpha is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160023/" 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/PMC4160023/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mukherjee, Sohini -- Zheng, Hui -- Derebe, Mehabaw G -- Callenberg, Keith M -- Partch, Carrie L -- Rollins, Darcy -- Propheter, Daniel C -- Rizo, Josep -- Grabe, Michael -- Jiang, Qiu-Xing -- Hooper, Lora V -- C06 RR30414/RR/NCRR NIH HHS/ -- F32 DK100074/DK/NIDDK NIH HHS/ -- GM093271/GM/NIGMS NIH HHS/ -- R01 DK070855/DK/NIDDK NIH HHS/ -- R01 NS040944/NS/NINDS NIH HHS/ -- R01 NS40944/NS/NINDS NIH HHS/ -- R01GM088745/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 2;505(7481):103-7. doi: 10.1038/nature12729. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Biological Sciences, University of Pittsburgh, and Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania 15261, USA. ; Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. ; Department of Biochemistry and Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biological Sciences, University of Pittsburgh, and Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania 15261, USA [2] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA. ; 1] Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2]. ; 1] Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256734" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/chemistry/immunology/*metabolism/pharmacology ; Antigens, Neoplasm/chemistry/immunology/*metabolism ; Biomarkers, Tumor/antagonists & inhibitors/chemistry/immunology/*metabolism ; Cell Membrane Permeability/drug effects ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Gram-Negative Bacteria/drug effects/immunology/metabolism ; Humans ; Immunity, Mucosal/drug effects/immunology ; Intestines/*chemistry/immunology/microbiology ; Lectins, C-Type/antagonists & inhibitors/chemistry/immunology/*metabolism ; Lipopolysaccharides/pharmacology ; Listeria monocytogenes/drug effects/immunology/metabolism ; Microbial Viability/drug effects ; Models, Molecular ; Peptidoglycan/metabolism ; Phospholipids/metabolism ; Porins/antagonists & inhibitors/chemistry/*metabolism ; Symbiosis
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    Structural basis for Ca2+ selectivity of a voltage-gated calcium channel (2013)
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    Publication Date: 2013-11-26
    Description: Voltage-gated calcium (CaV) channels catalyse rapid, highly selective influx of Ca(2+) into cells despite a 70-fold higher extracellular concentration of Na(+). How CaV channels solve this fundamental biophysical problem remains unclear. Here we report physiological and crystallographic analyses of a calcium selectivity filter constructed in the homotetrameric bacterial NaV channel NaVAb. Our results reveal interactions of hydrated Ca(2+) with two high-affinity Ca(2+)-binding sites followed by a third lower-affinity site that would coordinate Ca(2+) as it moves inward. At the selectivity filter entry, Site 1 is formed by four carboxyl side chains, which have a critical role in determining Ca(2+) selectivity. Four carboxyls plus four backbone carbonyls form Site 2, which is targeted by the blocking cations Cd(2+) and Mn(2+), with single occupancy. The lower-affinity Site 3 is formed by four backbone carbonyls alone, which mediate exit into the central cavity. This pore architecture suggests a conduction pathway involving transitions between two main states with one or two hydrated Ca(2+) ions bound in the selectivity filter and supports a 'knock-off' mechanism of ion permeation through a stepwise-binding process. The multi-ion selectivity filter of our CaVAb model establishes a structural framework for understanding the mechanisms of ion selectivity and conductance by vertebrate CaV channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877713/" 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/PMC3877713/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Lin -- Gamal El-Din, Tamer M -- Payandeh, Jian -- Martinez, Gilbert Q -- Heard, Teresa M -- Scheuer, Todd -- Zheng, Ning -- Catterall, William A -- R01 HL112808/HL/NHLBI NIH HHS/ -- R01 HL117896/HL/NHLBI NIH HHS/ -- R01 NS015751/NS/NINDS NIH HHS/ -- R01HL112808/HL/NHLBI NIH HHS/ -- R01NS015751/NS/NINDS NIH HHS/ -- T32 GM008268/GM/NIGMS NIH HHS/ -- T32GM008268/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 2;505(7481):56-61. doi: 10.1038/nature12775. Epub 2013 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA [3]. ; 1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2]. ; 1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2] Department of Structural Biology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2] 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/24270805" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Biocatalysis ; Calcium/metabolism ; Calcium Channels/*chemistry/genetics/*metabolism ; Cations, Divalent/metabolism ; Crystallography, X-Ray ; Electric Conductivity ; *Ion Channel Gating ; Models, Biological ; Models, Molecular ; Structure-Activity Relationship ; Substrate Specificity
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    Structural basis of lentiviral subversion of a cellular protein degradation pathway (2013)
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    Publication Date: 2013-12-18
    Description: Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4(+) T cells by reducing the cellular deoxynucleoside 5'-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell's ubiquitination machinery to destroy the cell's protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell's normal protein degradation pathway to inactivate the cellular viral defence system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886899/" 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/PMC3886899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwefel, David -- Groom, Harriet C T -- Boucherit, Virginie C -- Christodoulou, Evangelos -- Walker, Philip A -- Stoye, Jonathan P -- Bishop, Kate N -- Taylor, Ian A -- 084955/Wellcome Trust/United Kingdom -- MC_U117512710/Medical Research Council/United Kingdom -- MC_U117565647/Medical Research Council/United Kingdom -- MC_U117592729/Medical Research Council/United Kingdom -- U117512710/Medical Research Council/United Kingdom -- U11756564/Medical Research Council/United Kingdom -- U117592729/Medical Research Council/United Kingdom -- England -- Nature. 2014 Jan 9;505(7482):234-8. doi: 10.1038/nature12815. Epub 2013 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. ; Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336198" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Carrier Proteins/chemistry/*metabolism ; Cercocebus atys/virology ; Crystallography, X-Ray ; HIV/*chemistry/*physiology ; Host-Pathogen Interactions ; Humans ; Models, Molecular ; Molecular Sequence Data ; Monomeric GTP-Binding Proteins/chemistry/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Proteolysis ; Simian Immunodeficiency Virus/chemistry/physiology ; Ubiquitination ; Viral Regulatory and Accessory Proteins/*chemistry/*metabolism ; vpr Gene Products, Human Immunodeficiency Virus/chemistry/metabolism
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    Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers (2013)
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    Publication Date: 2013-08-13
    Description: KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hatzivassiliou, Georgia -- Haling, Jacob R -- Chen, Huifen -- Song, Kyung -- Price, Steve -- Heald, Robert -- Hewitt, Joanne F M -- Zak, Mark -- Peck, Ariana -- Orr, Christine -- Merchant, Mark -- Hoeflich, Klaus P -- Chan, Jocelyn -- Luoh, Shiuh-Ming -- Anderson, Daniel J -- Ludlam, Mary J C -- Wiesmann, Christian -- Ultsch, Mark -- Friedman, Lori S -- Malek, Shiva -- Belvin, Marcia -- England -- Nature. 2013 Sep 12;501(7466):232-6. doi: 10.1038/nature12441. Epub 2013 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. hatzivassiliou.georgia@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23934108" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Azetidines/pharmacology ; Cell Survival/drug effects ; Clinical Trials as Topic ; Crystallography, X-Ray ; Enzyme Activation/drug effects ; Feedback, Physiological/drug effects ; Genes, ras/*genetics ; HCT116 Cells ; Humans ; MAP Kinase Signaling System/drug effects ; Mitogen-Activated Protein Kinase Kinases/*antagonists & ; inhibitors/chemistry/metabolism ; Models, Molecular ; Neoplasms/*enzymology/*genetics/pathology ; Oncogene Protein p21(ras)/*genetics ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Piperidines/pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins B-raf/genetics/*metabolism
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    The BC component of ABC toxins is an RHS-repeat-containing protein encapsulation device (2013)
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    Publication Date: 2013-08-06
    Description: The ABC toxin complexes produced by certain bacteria are of interest owing to their potent insecticidal activity and potential role in human disease. These complexes comprise at least three proteins (A, B and C), which must assemble to be fully toxic. The carboxy-terminal region of the C protein is the main cytotoxic component, and is poorly conserved between different toxin complexes. A general model of action has been proposed, in which the toxin complex binds to the cell surface via the A protein, is endocytosed, and subsequently forms a pH-triggered channel, allowing the translocation of C into the cytoplasm, where it can cause cytoskeletal disruption in both insect and mammalian cells. Toxin complexes have been visualized using single-particle electron microscopy, but no high-resolution structures of the components are available, and the role of the B protein in the mechanism of toxicity remains unknown. Here we report the three-dimensional structure of the complex formed between the B and C proteins, determined to 2.5 A by X-ray crystallography. These proteins assemble to form an unprecedented, large hollow structure that encapsulates and sequesters the cytotoxic, C-terminal region of the C protein like the shell of an egg. The shell is decorated on one end by a beta-propeller domain, which mediates attachment of the B-C heterodimer to the A protein in the native complex. The structure reveals how C auto-proteolyses when folded in complex with B. The C protein is the first example, to our knowledge, of a structure that contains rearrangement hotspot (RHS) repeats, and illustrates a marked structural architecture that is probably conserved across both this widely distributed bacterial protein family and the related eukaryotic tyrosine-aspartate (YD)-repeat-containing protein family, which includes the teneurins. The structure provides the first clues about the function of these protein repeat families, and suggests a generic mechanism for protein encapsulation and delivery.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Busby, Jason N -- Panjikar, Santosh -- Landsberg, Michael J -- Hurst, Mark R H -- Lott, J Shaun -- England -- Nature. 2013 Sep 26;501(7468):547-50. doi: 10.1038/nature12465. Epub 2013 Aug 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉AgResearch Structural Biology Laboratory, School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23913273" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Bacterial Toxins/*chemistry/metabolism ; Consensus Sequence ; Conserved Sequence ; Crystallography, X-Ray ; Insecticides/chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Subunits/chemistry/metabolism ; Proteolysis ; *Repetitive Sequences, Amino Acid ; Yersinia/*chemistry
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    Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP (2013)
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    Publication Date: 2013-10-22
    Description: Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-kappaB activation and protection against tumour necrosis factor-alpha-induced apoptosis. They are synthesized by HOIP, which belongs to the RBR (RING-between-RING) family of E3 ligases and is the catalytic component of LUBAC (linear ubiquitin chain assembly complex), a multisubunit E3 ligase. RBR family members act as RING/HECT hybrids, employing RING1 to recognize ubiquitin-loaded E2 while a conserved cysteine in RING2 subsequently forms a thioester intermediate with the transferred or 'donor' ubiquitin. Here we report the crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin. The carboxy-terminal portion of HOIP adopts a novel fold that, together with a zinc-finger, forms a ubiquitin-binding platform that orients the acceptor ubiquitin and positions its alpha-amino group for nucleophilic attack on the E3 approximately ubiquitin thioester. The C-terminal tail of a second ubiquitin molecule is located in close proximity to the catalytic cysteine, providing a unique snapshot of the ubiquitin transfer complex containing both donor and acceptor ubiquitin. These interactions are required for activation of the NF-kappaB pathway in vivo, and they explain the determinants of linear ubiquitin chain specificity by LUBAC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838313/" 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/PMC3838313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stieglitz, Benjamin -- Rana, Rohini R -- Koliopoulos, Marios G -- Morris-Davies, Aylin C -- Schaeffer, Veronique -- Christodoulou, Evangelos -- Howell, Steven -- Brown, Nicholas R -- Dikic, Ivan -- Rittinger, Katrin -- 094112/Wellcome Trust/United Kingdom -- 250241/European Research Council/International -- MC_U117565398/Medical Research Council/United Kingdom -- U117565398/Medical Research Council/United Kingdom -- England -- Nature. 2013 Nov 21;503(7476):422-6. doi: 10.1038/nature12638. Epub 2013 Oct 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24141947" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; HeLa Cells ; Humans ; Models, Molecular ; Protein Conformation ; Substrate Specificity ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/*chemistry/*metabolism
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    Receptor binding by an H7N9 influenza virus from humans (2013)
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    Publication Date: 2013-06-22
    Description: Of the 132 people known to have been infected with H7N9 influenza viruses in China, 37 died, and many were severely ill. Infection seems to have involved contact with infected poultry. We have examined the receptor-binding properties of this H7N9 virus and compared them with those of an avian H7N3 virus. We find that the human H7 virus has significantly higher affinity for alpha-2,6-linked sialic acid analogues ('human receptor') than avian H7 while retaining the strong binding to alpha-2,3-linked sialic acid analogues ('avian receptor') characteristic of avian viruses. The human H7 virus does not, therefore, have the preference for human versus avian receptors characteristic of pandemic viruses. X-ray crystallography of the receptor-binding protein, haemagglutinin (HA), in complex with receptor analogues indicates that both human and avian receptors adopt different conformations when bound to human H7 HA than they do when bound to avian H7 HA. Human receptor bound to human H7 HA exits the binding site in a different direction to that seen in complexes formed by HAs from pandemic viruses and from an aerosol-transmissible H5 mutant. The human-receptor-binding properties of human H7 probably arise from the introduction of two bulky hydrophobic residues by the substitutions Gln226Leu and Gly186Val. The former is shared with the 1957 H2 and 1968 H3 pandemic viruses and with the aerosol-transmissible H5 mutant. We conclude that the human H7 virus has acquired some of the receptor-binding characteristics that are typical of pandemic viruses, but its retained preference for avian receptor may restrict its further evolution towards a virus that could transmit efficiently between humans, perhaps by binding to avian-receptor-rich mucins in the human respiratory tract rather than to cellular receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiong, Xiaoli -- Martin, Stephen R -- Haire, Lesley F -- Wharton, Stephen A -- Daniels, Rodney S -- Bennett, Michael S -- McCauley, John W -- Collins, Patrick J -- Walker, Philip A -- Skehel, John J -- Gamblin, Steven J -- MC_U117584222/Medical Research Council/United Kingdom -- MC_U117585868/Medical Research Council/United Kingdom -- U117512723/PHS HHS/ -- U117570592/PHS HHS/ -- U117584222/PHS HHS/ -- U117585868/PHS HHS/ -- England -- Nature. 2013 Jul 25;499(7459):496-9. doi: 10.1038/nature12372.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23787694" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Birds/metabolism/virology ; Crystallography, X-Ray ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry/metabolism ; Humans ; Influenza A Virus, H7N3 Subtype/metabolism ; Influenza A virus/chemistry/isolation & purification/*metabolism ; Influenza, Human/*virology ; Models, Molecular ; Mucins/chemistry/metabolism ; N-Acetylneuraminic Acid/analogs & derivatives/chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Receptors, Virus/chemistry/*metabolism
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    Functional and evolutionary insight from the crystal structure of rubella virus protein E1 (2013)
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    Publication Date: 2013-01-08
    Description: Little is known about the three-dimensional organization of rubella virus, which causes a relatively mild measles-like disease in children but leads to serious congenital health problems when contracted in utero. Although rubella virus belongs to the same family as the mosquito-borne alphaviruses, in many respects it is more similar to other aerosol-transmitted human viruses such as the agents of measles and mumps. Although the use of the triple MMR (measles, mumps and rubella) live vaccine has limited its incidence in western countries, congenital rubella syndrome remains an important health problem in the developing world. Here we report the 1.8 A resolution crystal structure of envelope glycoprotein E1, the main antigen and sole target of neutralizing antibodies against rubella virus. E1 is the main player during entry into target cells owing to its receptor-binding and membrane-fusion functions. The structure reveals the epitope and the neutralization mechanism of an important category of protecting antibodies against rubella infection. It also shows that rubella virus E1 is a class II fusion protein, which had hitherto only been structurally characterized for the arthropod-borne alphaviruses and flaviviruses. In addition, rubella virus E1 has an extensive membrane-fusion surface that includes a metal site, reminiscent of the T-cell immunoglobulin and mucin family of cellular proteins that bind phosphatidylserine lipids at the plasma membrane of cells undergoing apoptosis. Such features have not been seen in any fusion protein crystallized so far. Structural comparisons show that the class II fusion proteins from alphaviruses and flaviviruses, despite belonging to different virus families, are closer to each other than they are to rubella virus E1. This suggests that the constraints on arboviruses imposed by alternating cycles between vertebrates and arthropods resulted in more conservative evolution. By contrast, in the absence of this constraint, the strictly human rubella virus seems to have drifted considerably into a unique niche as sole member of the Rubivirus genus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DuBois, Rebecca M -- Vaney, Marie-Christine -- Tortorici, M Alejandra -- Kurdi, Rana Al -- Barba-Spaeth, Giovanna -- Krey, Thomas -- Rey, Felix A -- England -- Nature. 2013 Jan 24;493(7433):552-6. doi: 10.1038/nature11741. Epub 2013 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Departement de Virologie, Unite de Virologie Structurale and CNRS URA 3015, F-75724 Paris Cedex 15, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23292515" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; *Biological Evolution ; Cell Line ; Crystallography, X-Ray ; Drosophila melanogaster ; Evolution, Molecular ; Hydrogen-Ion Concentration ; Liposomes/chemistry/metabolism ; Membrane Fusion ; Metals/metabolism ; Models, Molecular ; Protein Multimerization ; Rubella Syndrome, Congenital/virology ; Rubella virus/*chemistry/physiology ; Viral Envelope Proteins/*chemistry/genetics/*metabolism/ultrastructure
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    A two-domain elevator mechanism for sodium/proton antiport (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-03
    Description: Sodium/proton (Na(+)/H(+)) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets. The best understood model system for Na(+)/H(+) antiport is NhaA from Escherichia coli, for which both electron microscopy and crystal structures are available. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein. Like many Na(+)/H(+) antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur. The only reported NhaA crystal structure so far is of the low pH inactivated form. Here we describe the active-state structure of a Na(+)/H(+) antiporter, NapA from Thermus thermophilus, at 3 A resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20 degrees against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second, Na(+)/H(+) antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914025/" 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/PMC3914025/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Chiara -- Kang, Hae Joo -- von Ballmoos, Christoph -- Newstead, Simon -- Uzdavinys, Povilas -- Dotson, David L -- Iwata, So -- Beckstein, Oliver -- Cameron, Alexander D -- Drew, David -- 062164/Z/00/Z/Wellcome Trust/United Kingdom -- 099165/Wellcome Trust/United Kingdom -- BB/G02325/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0900399/Medical Research Council/United Kingdom -- G0900990/Medical Research Council/United Kingdom -- England -- Nature. 2013 Sep 26;501(7468):573-7. doi: 10.1038/nature12484. Epub 2013 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995679" target="_blank"〉PubMed〈/a〉
    Keywords: Aspartic Acid/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry ; Hydrogen-Ion Concentration ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Multimerization ; Protein Structure, Tertiary ; Protons ; Sodium/metabolism ; Sodium-Hydrogen Antiporter/*chemistry/genetics/metabolism ; Static Electricity ; Thermus thermophilus/*chemistry/genetics
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    Gating of the TrkH ion channel by its associated RCK protein TrkA (2013)
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    Publication Date: 2013-04-20
    Description: TrkH belongs to a superfamily of K(+) transport proteins required for growth of bacteria in low external K(+) concentrations. The crystal structure of TrkH from Vibrio parahaemolyticus showed that TrkH resembles a K(+) channel and may have a gating mechanism substantially different from K(+) channels. TrkH assembles with TrkA, a cytosolic protein comprising two RCK (regulate the conductance of K(+)) domains, which are found in certain K(+) channels and control their gating. However, fundamental questions on whether TrkH is an ion channel and how it is regulated by TrkA remain unresolved. Here we show single-channel activity of TrkH that is upregulated by ATP via TrkA. We report two structures of the tetrameric TrkA ring, one in complex with TrkH and one in isolation, in which the ring assumes two markedly different conformations. These results suggest a mechanism for how ATP increases TrkH activity by inducing conformational changes in TrkA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726529/" 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/PMC3726529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yu -- Pan, Yaping -- Huang, Hua -- Jin, Xiangshu -- Levin, Elena J -- Kloss, Brian -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM098878/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM095315/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):317-22. doi: 10.1038/nature12056.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598339" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Electric Conductivity ; *Ion Channel Gating ; Ion Transport ; Models, Molecular ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Vibrio parahaemolyticus
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    K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions (2013)
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    Publication Date: 2013-11-22
    Description: Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274051/" 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/PMC4274051/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ostrem, Jonathan M -- Peters, Ulf -- Sos, Martin L -- Wells, James A -- Shokat, Kevan M -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):548-51. doi: 10.1038/nature12796. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256730" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Allosteric Site/*drug effects ; Apoptosis/drug effects ; Cell Line, Tumor ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Drug Discovery ; Genes, ras/genetics ; Guanosine Diphosphate/*metabolism ; Guanosine Triphosphate/*metabolism ; Humans ; Lung Neoplasms/drug therapy/metabolism/pathology ; Models, Molecular ; Mutant Proteins/*antagonists & inhibitors/genetics/*metabolism ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Static Electricity ; Substrate Specificity ; raf Kinases/metabolism
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    Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-05
    Description: (S)-2-hydroxypropylphosphonate ((S)-2-HPP) epoxidase (HppE) is a mononuclear non-haem-iron-dependent enzyme responsible for the final step in the biosynthesis of the clinically useful antibiotic fosfomycin. Enzymes of this class typically catalyse oxygenation reactions that proceed via the formation of substrate radical intermediates. By contrast, HppE catalyses an unusual dehydrogenation reaction while converting the secondary alcohol of (S)-2-HPP to the epoxide ring of fosfomycin. Here we show that HppE also catalyses a biologically unprecedented 1,2-phosphono migration with the alternative substrate (R)-1-HPP. This transformation probably involves an intermediary carbocation, based on observations with additional substrate analogues, such as (1R)-1-hydroxyl-2-aminopropylphosphonate, and model reactions for both radical- and carbocation-mediated migration. The ability of HppE to catalyse distinct reactions depending on the regio- and stereochemical properties of the substrate is given a structural basis using X-ray crystallography. These results provide compelling evidence for the formation of a substrate-derived cation intermediate in the catalytic cycle of a mononuclear non-haem-iron-dependent enzyme. The underlying chemistry of this unusual phosphono migration may represent a new paradigm for the in vivo construction of phosphonate-containing natural products that can be exploited for the preparation of new phosphonate derivatives.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725809/" 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/PMC3725809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Wei-chen -- Dey, Mishtu -- Liu, Pinghua -- Mansoorabadi, Steven O -- Moon, Sung-Ju -- Zhao, Zongbao K -- Drennan, Catherine L -- Liu, Hung-wen -- GM040541/GM/NIGMS NIH HHS/ -- R01 GM040541/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 4;496(7443):114-8. doi: 10.1038/nature11998.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, 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/23552950" target="_blank"〉PubMed〈/a〉
    Keywords: *Biocatalysis ; Biological Products/chemistry/metabolism ; Crystallography, X-Ray ; Fosfomycin/*biosynthesis/chemistry/metabolism ; Hydrogenation ; Iron ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Nonheme Iron Proteins/chemistry/metabolism ; Organophosphonates/chemistry/*metabolism ; Oxidoreductases/chemistry/*metabolism ; Substrate Specificity ; Time Factors
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    Structural basis for molecular recognition of folic acid by folate receptors (2013)
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    Publication Date: 2013-07-16
    Description: Folate receptors (FRalpha, FRbeta and FRgamma) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRalpha, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRalpha antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FRalpha in complex with folic acid at 2.8 A resolution. FRalpha has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRalpha binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Chen -- Ke, Jiyuan -- Zhou, X Edward -- Yi, Wei -- Brunzelle, Joseph S -- Li, Jun -- Yong, Eu-Leong -- Xu, H Eric -- Melcher, Karsten -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 GM102545/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Aug 22;500(7463):486-9. doi: 10.1038/nature12327. Epub 2013 Jul 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program for Structural Biology and Drug Discovery, Van Andel Research Institute, 333 Bostwick Avenue North East, Grand Rapids, Michigan 49503, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23851396" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites/genetics ; Crystallography, X-Ray ; Folate Receptor 1/*chemistry/genetics/*metabolism ; Folic Acid/chemistry/*metabolism ; Humans ; Ligands ; Models, Molecular ; Mutation ; Protein Binding ; Structure-Activity Relationship
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    Crystal structure of a nitrate/nitrite exchanger (2013)
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    Publication Date: 2013-05-15
    Description: Mineral nitrogen in nature is often found in the form of nitrate (NO3(-)). Numerous microorganisms evolved to assimilate nitrate and use it as a major source of mineral nitrogen uptake. Nitrate, which is central in nitrogen metabolism, is first reduced to nitrite (NO2(-)) through a two-electron reduction reaction. The accumulation of cellular nitrite can be harmful because nitrite can be reduced to the cytotoxic nitric oxide. Instead, nitrite is rapidly removed from the cell by channels and transporters, or reduced to ammonium or dinitrogen through the action of assimilatory enzymes. Despite decades of effort no structure is currently available for any nitrate transport protein and the mechanism by which nitrate is transported remains largely unknown. Here we report the structure of a bacterial nitrate/nitrite transport protein, NarK, from Escherichia coli, with and without substrate. The structures reveal a positively charged substrate-translocation pathway lacking protonatable residues, suggesting that NarK functions as a nitrate/nitrite exchanger and that protons are unlikely to be co-transported. Conserved arginine residues comprise the substrate-binding pocket, which is formed by association of helices from the two halves of NarK. Key residues that are important for substrate recognition and transport are identified and related to extensive mutagenesis and functional studies. We propose that NarK exchanges nitrate for nitrite by a rocker switch mechanism facilitated by inter-domain hydrogen bond networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669217/" 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/PMC3669217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hongjin -- Wisedchaisri, Goragot -- Gonen, Tamir -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 30;497(7451):647-51. doi: 10.1038/nature12139. Epub 2013 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23665960" target="_blank"〉PubMed〈/a〉
    Keywords: Anion Transport Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Hydrogen Bonding ; Models, Molecular ; Nitrates/*metabolism ; Nitrites/*metabolism ; Protein Conformation ; Protons
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    Structural and energetic basis of folded-protein transport by the FimD usher (2013)
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    Publication Date: 2013-04-13
    Description: Type 1 pili, produced by uropathogenic Escherichia coli, are multisubunit fibres crucial in recognition of and adhesion to host tissues. During pilus biogenesis, subunits are recruited to an outer membrane assembly platform, the FimD usher, which catalyses their polymerization and mediates pilus secretion. The recent determination of the crystal structure of an initiation complex provided insight into the initiation step of pilus biogenesis resulting in pore activation, but very little is known about the elongation steps that follow. Here, to address this question, we determine the structure of an elongation complex in which the tip complex assembly composed of FimC, FimF, FimG and FimH passes through FimD. This structure demonstrates the conformational changes required to prevent backsliding of the nascent pilus through the FimD pore and also reveals unexpected properties of the usher pore. We show that the circular binding interface between the pore lumen and the folded substrate participates in transport by defining a low-energy pathway along which the nascent pilus polymer is guided during secretion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673227/" 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/PMC3673227/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geibel, Sebastian -- Procko, Erik -- Hultgren, Scott J -- Baker, David -- Waksman, Gabriel -- 85602/Medical Research Council/United Kingdom -- AI029549/AI/NIAID NIH HHS/ -- G0800002/Medical Research Council/United Kingdom -- G0800002(85602)/Medical Research Council/United Kingdom -- P41 GM103533/GM/NIGMS NIH HHS/ -- P41GM103533/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 11;496(7444):243-6. doi: 10.1038/nature12007.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Structural and Molecular Biology, University College London and Birkbeck College, Malet Street, London WC1E 7HX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579681" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Fimbriae Proteins/*chemistry/*metabolism ; Fimbriae, Bacterial/chemistry/metabolism ; Models, Molecular ; Protein Conformation ; *Protein Folding ; Protein Stability ; Protein Transport ; Thermodynamics
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    X-ray structure of dopamine transporter elucidates antidepressant mechanism (2013)
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    Publication Date: 2013-09-17
    Description: Antidepressants targeting Na(+)/Cl(-)-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 A resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904663/" 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/PMC3904663/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penmatsa, Aravind -- Wang, Kevin H -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):85-90. doi: 10.1038/nature12533. Epub 2013 Sep 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Vollum Institute, Oregon Health & Science University, 3181 South West Sam Jackson Park Road, Portland, Oregon 97239, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24037379" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidepressive Agents, Tricyclic/chemistry/metabolism/*pharmacology ; Bacterial Proteins/chemistry ; Binding Sites ; Cholesterol/chemistry/metabolism ; Crystallization ; Crystallography, X-Ray ; Dopamine Plasma Membrane Transport Proteins/*chemistry/metabolism ; Drosophila melanogaster/*chemistry ; Ions/chemistry/metabolism ; Models, Molecular ; Nortriptyline/chemistry/metabolism/*pharmacology ; Protein Conformation ; Protein Stability ; Structure-Activity Relationship ; Temperature
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    Structural mechanism of ligand activation in human GABA(B) receptor (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-12-07
    Description: Human GABA(B) (gamma-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes on agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, whereas an agonist induces its domain closure for activation. Our data reveal a unique activation mechanism for GABA(B) receptor that involves the formation of a novel heterodimer interface between subunits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865065/" 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/PMC3865065/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geng, Yong -- Bush, Martin -- Mosyak, Lidia -- Wang, Feng -- Fan, Qing R -- R01 GM088454/GM/NIGMS NIH HHS/ -- R01GM088454/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Dec 12;504(7479):254-9. doi: 10.1038/nature12725. Epub 2013 Dec 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Columbia University, New York, New York 10032, USA. ; 1] Department of Pharmacology, Columbia University, New York, New York 10032, USA [2] Department of Pathology & Cell Biology, 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/24305054" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; GABA-B Receptor Agonists/pharmacology ; GABA-B Receptor Antagonists/pharmacology ; Humans ; Ligands ; Models, Molecular ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Receptors, GABA-B/*chemistry/*metabolism ; Substrate Specificity
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    Crystal structure of pre-activated arrestin p44 (2013)
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    Publication Date: 2013-04-23
    Description: Arrestins interact with G-protein-coupled receptors (GPCRs) to block interaction with G proteins and initiate G-protein-independent signalling. Arrestins have a bi-lobed structure that is stabilized by a long carboxy-terminal tail (C-tail), and displacement of the C-tail by receptor-attached phosphates activates arrestins for binding active GPCRs. Structures of the inactive state of arrestin are available, but it is not known how C-tail displacement activates arrestin for receptor coupling. Here we present a 3.0 A crystal structure of the bovine arrestin-1 splice variant p44, in which the activation step is mimicked by C-tail truncation. The structure of this pre-activated arrestin is profoundly different from the basal state and gives insight into the activation mechanism. p44 displays breakage of the central polar core and other interlobe hydrogen-bond networks, leading to a approximately 21 degrees rotation of the two lobes as compared to basal arrestin-1. Rearrangements in key receptor-binding loops in the central crest region include the finger loop, loop 139 (refs 8, 10, 11) and the sequence Asp 296-Asn 305 (or gate loop), here identified as controlling the polar core. We verified the role of these conformational alterations in arrestin activation and receptor binding by site-directed fluorescence spectroscopy. The data indicate a mechanism for arrestin activation in which C-tail displacement releases critical central-crest loops from restricted to extended receptor-interacting conformations. In parallel, increased flexibility between the two lobes facilitates a proper fitting of arrestin to the active receptor surface. Our results provide a snapshot of an arrestin ready to bind the active receptor, and give an insight into the role of naturally occurring truncated arrestins in the visual system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Yong Ju -- Hofmann, Klaus Peter -- Ernst, Oliver P -- Scheerer, Patrick -- Choe, Hui-Woog -- Sommer, Martha E -- England -- Nature. 2013 May 2;497(7447):142-6. doi: 10.1038/nature12133. Epub 2013 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Medizinische Physik und Biophysik (CC2), Charite-Universitatsmedizin Berlin, Chariteplatz 1, D-10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23604253" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Animals ; Arrestins/*chemistry/genetics/*metabolism ; Cattle ; Crystallography, X-Ray ; Hydrogen Bonding ; Models, Molecular ; Molecular Weight ; Protein Conformation ; Protein Isoforms/*chemistry/genetics/*metabolism ; Rotation ; Sequence Deletion ; Static Electricity
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    Chasing acyl carrier protein through a catalytic cycle of lipid A production (2013)
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    Publication Date: 2013-11-08
    Description: Acyl carrier protein represents one of the most highly conserved proteins across all domains of life and is nature's way of transporting hydrocarbon chains in vivo. Notably, type II acyl carrier proteins serve as a crucial interaction hub in primary cellular metabolism by communicating transiently between partner enzymes of the numerous biosynthetic pathways. However, the highly transient nature of such interactions and the inherent conformational mobility of acyl carrier protein have stymied previous attempts to visualize structurally acyl carrier protein tied to an overall catalytic cycle. This is essential to understanding a fundamental aspect of cellular metabolism leading to compounds that are not only useful to the cell, but also of therapeutic value. For example, acyl carrier protein is central to the biosynthesis of the lipid A (endotoxin) component of lipopolysaccharides in Gram-negative microorganisms, which is required for their growth and survival, and is an activator of the mammalian host's immune system, thus emerging as an important therapeutic target. During lipid A synthesis (Raetz pathway), acyl carrier protein shuttles acyl intermediates linked to its prosthetic 4'-phosphopantetheine group among four acyltransferases, including LpxD. Here we report the crystal structures of three forms of Escherichia coli acyl carrier protein engaging LpxD, which represent stalled substrate and liberated products along the reaction coordinate. The structures show the intricate interactions at the interface that optimally position acyl carrier protein for acyl delivery and that directly involve the pantetheinyl group. Conformational differences among the stalled acyl carrier proteins provide the molecular basis for the association-dissociation process. An unanticipated conformational shift of 4'-phosphopantetheine groups within the LpxD catalytic chamber shows an unprecedented role of acyl carrier protein in product release.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947097/" 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/PMC3947097/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masoudi, Ali -- Raetz, Christian R H -- Zhou, Pei -- Pemble, Charles W 4th -- AI-055588/AI/NIAID NIH HHS/ -- GM-51310/GM/NIGMS NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- R01 AI055588/AI/NIAID NIH HHS/ -- R01 GM051310/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 16;505(7483):422-6. doi: 10.1038/nature12679. Epub 2013 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA [2]. ; 1] Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Duke Macromolecular Crystallography Center, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24196711" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Carrier Protein/*chemistry/*metabolism ; Acyltransferases/chemistry/metabolism ; *Biocatalysis ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Hydrolysis ; Lipid A/*biosynthesis/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation
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    Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA (2013)
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    Publication Date: 2013-11-19
    Description: Splicing of precursor messenger RNA (pre-mRNA) in eukaryotic cells is carried out by the spliceosome, which consists of five small nuclear ribonucleoproteins (snRNPs) and a number of accessory factors and enzymes. Each snRNP contains a ring-shaped subcomplex of seven proteins and a specific RNA molecule. The U6 snRNP contains a unique heptameric Lsm protein complex, which specifically recognizes the U6 small nuclear RNA at its 3' end. Here we report the crystal structures of the heptameric Lsm complex, both by itself and in complex with a 3' fragment of U6 snRNA, at 2.8 A resolution. Each of the seven Lsm proteins interacts with two neighbouring Lsm components to form a doughnut-shaped assembly, with the order Lsm3-2-8-4-7-5-6. The four uridine nucleotides at the 3' end of U6 snRNA are modularly recognized by Lsm3, Lsm2, Lsm8 and Lsm4, with the uracil base specificity conferred by a highly conserved asparagine residue. The uracil base at the extreme 3' end is sandwiched by His 36 and Arg 69 from Lsm3, through pi-pi and cation-pi interactions, respectively. The distinctive end-recognition of U6 snRNA by the Lsm complex contrasts with RNA binding by the Sm complex in the other snRNPs. The structural features and associated biochemical analyses deepen mechanistic understanding of the U6 snRNP function in pre-mRNA splicing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Lijun -- Hang, Jing -- Zhou, Yulin -- Wan, Ruixue -- Lu, Guifeng -- Yin, Ping -- Yan, Chuangye -- Shi, Yigong -- England -- Nature. 2014 Feb 6;506(7486):116-20. doi: 10.1038/nature12803. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [3]. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China. ; State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China. ; Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China. ; 1] Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China [2] Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240276" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Asparagine/chemistry ; Base Sequence ; Crystallography, X-Ray ; Histidine/chemistry ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/*chemistry/metabolism ; Protein Binding ; Protein Structure, Quaternary ; RNA, Small Nuclear/*chemistry/*genetics/metabolism ; RNA-Binding Proteins/*chemistry/metabolism ; Ribonucleoproteins, Small Nuclear/chemistry/metabolism ; Saccharomyces cerevisiae/chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; Uracil/chemistry/metabolism
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