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  • Models, Molecular  (185)
  • Phylogeny
  • Nature Publishing Group (NPG)  (262)
  • American Institute of Physics (AIP)
  • Springer
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  • 1990-1994
  • 2011  (129)
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  • 1
    Publication Date: 2011-02-19
    Description: The deep-water Avalon biota (about 579 to 565 million years old) is often regarded as the earliest-known fossil assemblage with macroscopic and morphologically complex life forms. It has been proposed that the rise of the Avalon biota was triggered by the oxygenation of mid-Ediacaran deep oceans. Here we report a diverse assemblage of morphologically differentiated benthic macrofossils that were preserved largely in situ as carbonaceous compressions in black shales of the Ediacaran Lantian Formation (southern Anhui Province, South China). The Lantian biota, probably older than and taxonomically distinct from the Avalon biota, suggests that morphological diversification of macroscopic eukaryotes may have occurred in the early Ediacaran Period, perhaps shortly after the Marinoan glaciation, and that the redox history of Ediacaran oceans was more complex than previously thought.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Xunlai -- Chen, Zhe -- Xiao, Shuhai -- Zhou, Chuanming -- Hua, Hong -- England -- Nature. 2011 Feb 17;470(7334):390-3. doi: 10.1038/nature09810.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Palaeobiology and Stratigraphy, Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences, Nanjing 210008, China. xlyuan@nigpas.ac.cn〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331041" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; *Biota ; *Body Size ; China ; Eukaryota/*classification/cytology/isolation & purification ; *Fossils ; Geologic Sediments ; History, Ancient ; Oceans and Seas ; Oxidation-Reduction ; Phylogeny ; Uncertainty
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  • 2
    Publication Date: 2011-06-15
    Description: Polyhydroxylated steroids are regulators of body shape and size in higher organisms. In metazoans, intracellular receptors recognize these molecules. Plants, however, perceive steroids at membranes, using the membrane-integral receptor kinase BRASSINOSTEROID INSENSITIVE 1 (BRI1). Here we report the structure of the Arabidopsis thaliana BRI1 ligand-binding domain, determined by X-ray diffraction at 2.5 A resolution. We find a superhelix of 25 twisted leucine-rich repeats (LRRs), an architecture that is strikingly different from the assembly of LRRs in animal Toll-like receptors. A 70-amino-acid island domain between LRRs 21 and 22 folds back into the interior of the superhelix to create a surface pocket for binding the plant hormone brassinolide. Known loss- and gain-of-function mutations map closely to the hormone-binding site. We propose that steroid binding to BRI1 generates a docking platform for a co-receptor that is required for receptor activation. Our findings provide insight into the activation mechanism of this highly expanded family of plant receptors that have essential roles in hormone, developmental and innate immunity signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280218/" 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/PMC3280218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hothorn, Michael -- Belkhadir, Youssef -- Dreux, Marlene -- Dabi, Tsegaye -- Noel, Joseph P -- Wilson, Ian A -- Chory, Joanne -- AI042266/AI/NIAID NIH HHS/ -- R01 AI042266/AI/NIAID NIH HHS/ -- R01 AI042266-05/AI/NIAID NIH HHS/ -- R37 AI042266/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 12;474(7352):467-71. doi: 10.1038/nature10153.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plant Biology Laboratory, The Salk Institute for Biological Studies, 10010 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/21666665" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/*chemistry/metabolism ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; Brassinosteroids ; Cholestanols/chemistry/*metabolism ; Crystallography, X-Ray ; Enzyme Activation ; Models, Molecular ; Molecular Sequence Data ; Plant Growth Regulators/chemistry/*metabolism ; Protein Binding ; Protein Kinases/*chemistry/*metabolism ; Protein Multimerization ; Protein Structure, Tertiary ; Steroids, Heterocyclic/chemistry/*metabolism ; Structure-Activity Relationship
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  • 3
    Publication Date: 2011-04-26
    Description: The spliceosome is a dynamic macromolecular machine that assembles on pre-messenger RNA substrates and catalyses the excision of non-coding intervening sequences (introns). Four of the five major components of the spliceosome, U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), contain seven Sm proteins (SmB/B', SmD1, SmD2, SmD3, SmE, SmF and SmG) in common. Following export of the U1, U2, U4 and U5 snRNAs to the cytoplasm, the seven Sm proteins, chaperoned by the survival of motor neurons (SMN) complex, assemble around a single-stranded, U-rich sequence called the Sm site in each small nuclear RNA (snRNA), to form the core domain of the respective snRNP particle. Core domain formation is a prerequisite for re-import into the nucleus, where these snRNPs mature via addition of their particle-specific proteins. Here we present a crystal structure of the U4 snRNP core domain at 3.6 A resolution, detailing how the Sm site heptad (AUUUUUG) binds inside the central hole of the heptameric ring of Sm proteins, interacting one-to-one with SmE-SmG-SmD3-SmB-SmD1-SmD2-SmF. An irregular backbone conformation of the Sm site sequence combined with the asymmetric structure of the heteromeric protein ring allows each base to interact in a distinct manner with four key residues at equivalent positions in the L3 and L5 loops of the Sm fold. A comparison of this structure with the U1 snRNP at 5.5 A resolution reveals snRNA-dependent structural changes outside the Sm fold, which may facilitate the binding of particle-specific proteins that are crucial to biogenesis of spliceosomal snRNPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103711/" 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/PMC3103711/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leung, Adelaine K W -- Nagai, Kiyoshi -- Li, Jade -- MC_U105184330/Medical Research Council/United Kingdom -- U.1051.04.016(78933)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 May 26;473(7348):536-9. doi: 10.1038/nature09956. Epub 2011 Apr 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21516107" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Nucleotides/chemistry/metabolism ; Protein Folding ; Protein Structure, Tertiary ; RNA/chemistry/metabolism ; Ribonucleoprotein, U1 Small Nuclear/chemistry ; Ribonucleoprotein, U4-U6 Small Nuclear/*biosynthesis/*chemistry/metabolism ; Spliceosomes/chemistry/metabolism ; Structure-Activity Relationship
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  • 4
    Publication Date: 2011-10-18
    Description: Hydrogenases are abundant enzymes that catalyse the reversible interconversion of H(2) into protons and electrons at high rates. Those hydrogenases maintaining their activity in the presence of O(2) are considered to be central to H(2)-based technologies, such as enzymatic fuel cells and for light-driven H(2) production. Despite comprehensive genetic, biochemical, electrochemical and spectroscopic investigations, the molecular background allowing a structural interpretation of how the catalytic centre is protected from irreversible inactivation by O(2) has remained unclear. Here we present the crystal structure of an O(2)-tolerant [NiFe]-hydrogenase from the aerobic H(2) oxidizer Ralstonia eutropha H16 at 1.5 A resolution. The heterodimeric enzyme consists of a large subunit harbouring the catalytic centre in the H(2)-reduced state and a small subunit containing an electron relay consisting of three different iron-sulphur clusters. The cluster proximal to the active site displays an unprecedented [4Fe-3S] structure and is coordinated by six cysteines. According to the current model, this cofactor operates as an electronic switch depending on the nature of the gas molecule approaching the active site. It serves as an electron acceptor in the course of H(2) oxidation and as an electron-delivering device upon O(2) attack at the active site. This dual function is supported by the capability of the novel iron-sulphur cluster to adopt three redox states at physiological redox potentials. The second structural feature is a network of extended water cavities that may act as a channel facilitating the removal of water produced at the [NiFe] active site. These discoveries will have an impact on the design of biological and chemical H(2)-converting catalysts that are capable of cycling H(2) in air.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fritsch, Johannes -- Scheerer, Patrick -- Frielingsdorf, Stefan -- Kroschinsky, Sebastian -- Friedrich, Barbel -- Lenz, Oliver -- Spahn, Christian M T -- England -- Nature. 2011 Oct 16;479(7372):249-52. doi: 10.1038/nature10505.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mikrobiologie, Institut fur Biologie, Humboldt-Universitat zu Berlin, Chausseestrasse 117, 10115 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22002606" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Cupriavidus necator/*enzymology ; Cysteine/metabolism ; Hydrogenase/*chemistry/metabolism ; Iron/analysis/*chemistry ; Iron-Sulfur Proteins/*chemistry/metabolism ; Models, Molecular ; Oxidation-Reduction ; Oxygen/*metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Protons ; Sulfur/analysis/*chemistry ; Water/chemistry/metabolism
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  • 5
    Publication Date: 2011-03-11
    Description: G-protein-coupled receptors (GPCRs) are seven transmembrane helix (TM) proteins that transduce signals into living cells by binding extracellular ligands and coupling to intracellular heterotrimeric G proteins (Galphabetagamma). The photoreceptor rhodopsin couples to transducin and bears its ligand 11-cis-retinal covalently bound via a protonated Schiff base to the opsin apoprotein. Absorption of a photon causes retinal cis/trans isomerization and generates the agonist all-trans-retinal in situ. After early photoproducts, the active G-protein-binding intermediate metarhodopsin II (Meta II) is formed, in which the retinal Schiff base is still intact but deprotonated. Dissociation of the proton from the Schiff base breaks a major constraint in the protein and enables further activating steps, including an outward tilt of TM6 and formation of a large cytoplasmic crevice for uptake of the interacting C terminus of the Galpha subunit. Owing to Schiff base hydrolysis, Meta II is short-lived and notoriously difficult to crystallize. We therefore soaked opsin crystals with all-trans-retinal to form Meta II, presuming that the crystal's high concentration of opsin in an active conformation (Ops*) may facilitate all-trans-retinal uptake and Schiff base formation. Here we present the 3.0 A and 2.85 A crystal structures, respectively, of Meta II alone or in complex with an 11-amino-acid C-terminal fragment derived from Galpha (GalphaCT2). GalphaCT2 binds in a large crevice at the cytoplasmic side, akin to the binding of a similar Galpha-derived peptide to Ops* (ref. 7). In the Meta II structures, the electron density from the retinal ligand seamlessly continues into the Lys 296 side chain, reflecting proper formation of the Schiff base linkage. The retinal is in a relaxed conformation and almost undistorted compared with pure crystalline all-trans-retinal. By comparison with early photoproducts we propose how retinal translocation and rotation induce the gross conformational changes characteristic for Meta II. The structures can now serve as models for the large GPCR family.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choe, Hui-Woog -- Kim, Yong Ju -- Park, Jung Hee -- Morizumi, Takefumi -- Pai, Emil F -- Krauss, Norbert -- Hofmann, Klaus Peter -- Scheerer, Patrick -- Ernst, Oliver P -- England -- Nature. 2011 Mar 31;471(7340):651-5. doi: 10.1038/nature09789. Epub 2011 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Medizinische Physik und Biophysik - CC2, Charite - Universitatsmedizin Berlin, Chariteplatz 1, D-10117 Berlin, Germany. hwchoe@jbnu.ac.kr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21389988" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Conserved Sequence ; Crystallization ; Crystallography, X-Ray ; GTP-Binding Protein alpha Subunits/chemistry/metabolism ; Ligands ; Models, Molecular ; Opsins/chemistry ; Peptide Fragments/chemistry/metabolism ; Protein Conformation ; Retinaldehyde/chemistry/metabolism ; Rhodopsin/*chemistry/*metabolism ; Schiff Bases/chemistry ; Static Electricity
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  • 6
    Publication Date: 2011-11-29
    Description: Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversible protein modification by O-linked N-acetylglucosamine (GlcNAc) is catalysed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). However, the significance of GlcNAcylation in chromatin reorganization remains elusive. Here we report that histone H2B is GlcNAcylated at residue S112 by OGT in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway (HBP). H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genome-wide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites co-localizing with H2B K120 monoubiquitination. These findings suggest that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujiki, Ryoji -- Hashiba, Waka -- Sekine, Hiroki -- Yokoyama, Atsushi -- Chikanishi, Toshihiro -- Ito, Saya -- Imai, Yuuki -- Kim, Jaehoon -- He, Housheng Hansen -- Igarashi, Katsuhide -- Kanno, Jun -- Ohtake, Fumiaki -- Kitagawa, Hirochika -- Roeder, Robert G -- Brown, Myles -- Kato, Shigeaki -- England -- Nature. 2011 Nov 27;480(7378):557-60. doi: 10.1038/nature10656.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22121020" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; HeLa Cells ; Histones/chemistry/genetics/*metabolism ; Humans ; Models, Molecular ; Mutation ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; Ubiquitination
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  • 7
    Publication Date: 2011-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouard, Tanguy -- England -- Nature. 2011 Mar 10;471(7337):151-3. doi: 10.1038/471151a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390105" target="_blank"〉PubMed〈/a〉
    Keywords: CREB-Binding Protein/metabolism ; Calcineurin/chemistry/metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Computational Biology ; Crystallization ; Cyclic AMP Response Element-Binding Protein/chemistry/metabolism ; Cyclin-Dependent Kinase Inhibitor Proteins/chemistry/metabolism ; F-Box Proteins/chemistry/metabolism ; Humans ; Models, Biological ; Models, Molecular ; Pliability ; Protein Conformation ; Protein Folding ; *Protein Unfolding ; Proteins/*chemistry/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/metabolism ; Structure-Activity Relationship ; Tumor Suppressor Protein p53/chemistry/metabolism ; Ubiquitin-Protein Ligases/chemistry/metabolism
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  • 8
    Publication Date: 2011-10-14
    Description: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering approximately 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for approximately 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207357/" 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/PMC3207357/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindblad-Toh, Kerstin -- Garber, Manuel -- Zuk, Or -- Lin, Michael F -- Parker, Brian J -- Washietl, Stefan -- Kheradpour, Pouya -- Ernst, Jason -- Jordan, Gregory -- Mauceli, Evan -- Ward, Lucas D -- Lowe, Craig B -- Holloway, Alisha K -- Clamp, Michele -- Gnerre, Sante -- Alfoldi, Jessica -- Beal, Kathryn -- Chang, Jean -- Clawson, Hiram -- Cuff, James -- Di Palma, Federica -- Fitzgerald, Stephen -- Flicek, Paul -- Guttman, Mitchell -- Hubisz, Melissa J -- Jaffe, David B -- Jungreis, Irwin -- Kent, W James -- Kostka, Dennis -- Lara, Marcia -- Martins, Andre L -- Massingham, Tim -- Moltke, Ida -- Raney, Brian J -- Rasmussen, Matthew D -- Robinson, Jim -- Stark, Alexander -- Vilella, Albert J -- Wen, Jiayu -- Xie, Xiaohui -- Zody, Michael C -- Broad Institute Sequencing Platform and Whole Genome Assembly Team -- Baldwin, Jen -- Bloom, Toby -- Chin, Chee Whye -- Heiman, Dave -- Nicol, Robert -- Nusbaum, Chad -- Young, Sarah -- Wilkinson, Jane -- Worley, Kim C -- Kovar, Christie L -- Muzny, Donna M -- Gibbs, Richard A -- Baylor College of Medicine Human Genome Sequencing Center Sequencing Team -- Cree, Andrew -- Dihn, Huyen H -- Fowler, Gerald -- Jhangiani, Shalili -- Joshi, Vandita -- Lee, Sandra -- Lewis, Lora R -- Nazareth, Lynne V -- Okwuonu, Geoffrey -- Santibanez, Jireh -- Warren, Wesley C -- Mardis, Elaine R -- Weinstock, George M -- Wilson, Richard K -- Genome Institute at Washington University -- Delehaunty, Kim -- Dooling, David -- Fronik, Catrina -- Fulton, Lucinda -- Fulton, Bob -- Graves, Tina -- Minx, Patrick -- Sodergren, Erica -- Birney, Ewan -- Margulies, Elliott H -- Herrero, Javier -- Green, Eric D -- Haussler, David -- Siepel, Adam -- Goldman, Nick -- Pollard, Katherine S -- Pedersen, Jakob S -- Lander, Eric S -- Kellis, Manolis -- 095908/Wellcome Trust/United Kingdom -- GM82901/GM/NIGMS NIH HHS/ -- R01 HG003474/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-09/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Oct 12;478(7370):476-82. doi: 10.1038/nature10530.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. kersli@broadinstitute.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993624" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Disease ; *Evolution, Molecular ; Exons/genetics ; Genome/*genetics ; Genome, Human/*genetics ; Genomics ; Health ; Humans ; Mammals/*genetics ; Molecular Sequence Annotation ; Phylogeny ; RNA/classification/genetics ; Selection, Genetic/genetics ; Sequence Alignment ; Sequence Analysis, DNA
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  • 9
    Publication Date: 2011-05-13
    Description: Protein translocation across the bacterial membrane, mediated by the secretory translocon SecYEG and the SecA ATPase, is enhanced by proton motive force and membrane-integrated SecDF, which associates with SecYEG. The role of SecDF has remained unclear, although it is proposed to function in later stages of translocation as well as in membrane protein biogenesis. Here, we determined the crystal structure of Thermus thermophilus SecDF at 3.3 A resolution, revealing a pseudo-symmetrical, 12-helix transmembrane domain belonging to the RND superfamily and two major periplasmic domains, P1 and P4. Higher-resolution analysis of the periplasmic domains suggested that P1, which binds an unfolded protein, undergoes functionally important conformational changes. In vitro analyses identified an ATP-independent step of protein translocation that requires both SecDF and proton motive force. Electrophysiological analyses revealed that SecDF conducts protons in a manner dependent on pH and the presence of an unfolded protein, with conserved Asp and Arg residues at the transmembrane interface between SecD and SecF playing essential roles in the movements of protons and preproteins. Therefore, we propose that SecDF functions as a membrane-integrated chaperone, powered by proton motive force, to achieve ATP-independent protein translocation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697915/" 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/PMC3697915/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsukazaki, Tomoya -- Mori, Hiroyuki -- Echizen, Yuka -- Ishitani, Ryuichiro -- Fukai, Shuya -- Tanaka, Takeshi -- Perederina, Anna -- Vassylyev, Dmitry G -- Kohno, Toshiyuki -- Maturana, Andres D -- Ito, Koreaki -- Nureki, Osamu -- R01 GM074840/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 May 11;474(7350):235-8. doi: 10.1038/nature09980.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, 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/21562494" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Arginine/metabolism ; Asparagine/metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Hydrogen-Ion Concentration ; Membrane Proteins/*chemistry/*metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Periplasm/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Transport ; Protein Unfolding ; Proton-Motive Force ; Static Electricity ; Structure-Activity Relationship ; Thermus thermophilus/*chemistry/cytology
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  • 10
    Publication Date: 2011-07-26
    Description: Mitochondrial uncoupling protein 2 (UCP2) is an integral membrane protein in the mitochondrial anion carrier protein family, the members of which facilitate the transport of small molecules across the mitochondrial inner membrane. When the mitochondrial respiratory complex pumps protons from the mitochondrial matrix to the intermembrane space, it builds up an electrochemical potential. A fraction of this electrochemical potential is dissipated as heat, in a process involving leakage of protons back to the matrix. This leakage, or 'uncoupling' of the proton electrochemical potential, is mediated primarily by uncoupling proteins. However, the mechanism of UCP-mediated proton translocation across the lipid bilayer is unknown. Here we describe a solution-NMR method for structural characterization of UCP2. The method, which overcomes some of the challenges associated with membrane-protein structure determination, combines orientation restraints derived from NMR residual dipolar couplings (RDCs) and semiquantitative distance restraints from paramagnetic relaxation enhancement (PRE) measurements. The local and secondary structures of the protein were determined by piecing together molecular fragments from the Protein Data Bank that best fit experimental RDCs from samples weakly aligned in a DNA nanotube liquid crystal. The RDCs also determine the relative orientation of the secondary structural segments, and the PRE restraints provide their spatial arrangement in the tertiary fold. UCP2 closely resembles the bovine ADP/ATP carrier (the only carrier protein of known structure), but the relative orientations of the helical segments are different, resulting in a wider opening on the matrix side of the inner membrane. Moreover, the nitroxide-labelled GDP binds inside the channel and seems to be closer to transmembrane helices 1-4. We believe that this biophysical approach can be applied to other membrane proteins and, in particular, to other mitochondrial carriers, not only for structure determination but also to characterize various conformational states of these proteins linked to substrate transport.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150631/" 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/PMC3150631/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berardi, Marcelo J -- Shih, William M -- Harrison, Stephen C -- Chou, James J -- 1DP2OD004641/OD/NIH HHS/ -- 1U54GM094608/GM/NIGMS NIH HHS/ -- R21 DK075963/DK/NIDDK NIH HHS/ -- R21 DK075963-01/DK/NIDDK NIH HHS/ -- R21 DK075963-02/DK/NIDDK NIH HHS/ -- U54 GM094608/GM/NIGMS NIH HHS/ -- U54 GM094608-01/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 24;476(7358):109-13. doi: 10.1038/nature10257.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jack and Eileen Connors Structural Biology Laboratory, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21785437" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine Nucleotide Translocator 1/chemistry/metabolism ; Animals ; Binding Sites ; Cattle ; Databases, Protein ; Guanosine Diphosphate/chemistry/metabolism ; Ion Channels/*chemistry/metabolism ; Mice ; Mitochondrial ADP, ATP Translocases/chemistry ; Mitochondrial Proteins/*chemistry/metabolism ; Models, Molecular ; Nitrogen Oxides/chemistry/metabolism ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Protein Conformation
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  • 11
    Publication Date: 2011-04-09
    Description: M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268815/" 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/PMC3268815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macheboeuf, Pauline -- Buffalo, Cosmo -- Fu, Chi-yu -- Zinkernagel, Annelies S -- Cole, Jason N -- Johnson, John E -- Nizet, Victor -- Ghosh, Partho -- R01 AI052453/AI/NIAID NIH HHS/ -- R01 AI052453-10/AI/NIAID NIH HHS/ -- R01 AI077780/AI/NIAID NIH HHS/ -- R01 AI077780-03/AI/NIAID NIH HHS/ -- R01 GM54076/GM/NIGMS NIH HHS/ -- R21 AI071167/AI/NIAID NIH HHS/ -- T32 GM007240/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):64-8. doi: 10.1038/nature09967.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475196" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/chemistry/*metabolism/ultrastructure ; Binding Sites ; Crystallography, X-Ray ; Fibrinogen/*chemistry/metabolism/ultrastructure ; Humans ; Models, Molecular ; Neutrophil Activation ; Protein Binding ; Protein Conformation ; Shock, Septic/microbiology/physiopathology ; Streptococcus pyogenes/chemistry/*pathogenicity ; Virulence ; Virulence Factors/chemistry/*metabolism
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  • 12
    Publication Date: 2011-05-27
    Description: Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12 years of systematic surveillance in this region, supplemented with data stretching back 34 years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vijaykrishna, Dhanasekaran -- Smith, Gavin J D -- Pybus, Oliver G -- Zhu, Huachen -- Bhatt, Samir -- Poon, Leo L M -- Riley, Steven -- Bahl, Justin -- Ma, Siu K -- Cheung, Chung L -- Perera, Ranawaka A P M -- Chen, Honglin -- Shortridge, Kennedy F -- Webby, Richard J -- Webster, Robert G -- Guan, Yi -- Peiris, J S Malik -- HHSN26600700005C/PHS HHS/ -- MC_G0902096/Medical Research Council/United Kingdom -- England -- Nature. 2011 May 26;473(7348):519-22. doi: 10.1038/nature10004.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Emerging Infectious Diseases & Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614079" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/virology ; *Evolution, Molecular ; Female ; Hong Kong/epidemiology ; Humans ; Influenza A Virus, H1N1 Subtype/classification/genetics/isolation & ; purification/*physiology ; Influenza in Birds/transmission/virology ; Influenza, Human/epidemiology/transmission/virology ; Male ; Molecular Epidemiology ; Molecular Sequence Data ; Orthomyxoviridae Infections/epidemiology/transmission/*veterinary/virology ; Phylogeny ; Population Surveillance ; Reassortant Viruses/genetics/immunology/isolation & purification/physiology ; Swine/blood/*virology ; Swine Diseases/blood/epidemiology/*transmission/*virology ; Zoonoses/epidemiology/transmission/*virology
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  • 13
    Publication Date: 2011-03-23
    Description: The nucleobase/ascorbate transporter (NAT) proteins, also known as nucleobase/cation symporter 2 (NCS2) proteins, are responsible for the uptake of nucleobases in all kingdoms of life and for the transport of vitamin C in mammals. Despite functional characterization of the NAT family members in bacteria, fungi and mammals, detailed structural information remains unavailable. Here we report the crystal structure of a representative NAT protein, the Escherichia coli uracil/H(+) symporter UraA, in complex with uracil at a resolution of 2.8 A. UraA has a novel structural fold, with 14 transmembrane segments (TMs) divided into two inverted repeats. A pair of antiparallel beta-strands is located between TM3 and TM10 and has an important role in structural organization and substrate recognition. The structure is spatially arranged into a core domain and a gate domain. Uracil, located at the interface between the two domains, is coordinated mainly by residues from the core domain. Structural analysis suggests that alternating access of the substrate may be achieved through conformational changes of the gate domain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Feiran -- Li, Shuo -- Jiang, Yang -- Jiang, Jing -- Fan, He -- Lu, Guifeng -- Deng, Dong -- Dang, Shangyu -- Zhang, Xu -- Wang, Jiawei -- Yan, Nieng -- England -- Nature. 2011 Apr 14;472(7342):243-6. doi: 10.1038/nature09885. Epub 2011 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21423164" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Transport ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Hydrogen Bonding ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protons ; Structure-Activity Relationship ; Uracil/chemistry/*metabolism
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  • 14
    Publication Date: 2011-02-11
    Description: The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schreiber, Anne -- Stengel, Florian -- Zhang, Ziguo -- Enchev, Radoslav I -- Kong, Eric H -- Morris, Edward P -- Robinson, Carol V -- da Fonseca, Paula C A -- Barford, David -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Feb 10;470(7333):227-32. doi: 10.1038/nature09756.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307936" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Animals ; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome ; Biocatalysis ; Cell Line ; Holoenzymes/chemistry/metabolism/ultrastructure ; Mass Spectrometry ; Microscopy, Electron ; Models, Molecular ; Molecular Weight ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/isolation & purification/metabolism ; Recombinant Proteins/chemistry/metabolism/ultrastructure ; Saccharomyces cerevisiae/chemistry/genetics ; Saccharomyces cerevisiae Proteins/chemistry/isolation & ; purification/metabolism/ultrastructure ; Scattering, Radiation ; Schizosaccharomyces/chemistry ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/*chemistry/*metabolism/ultrastructure ; Ubiquitination
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  • 15
    Publication Date: 2011-05-27
    Description: Anomalocaridids, giant lightly sclerotized invertebrate predators, occur in a number of exceptionally preserved early and middle Cambrian (542-501 million years ago) biotas and have come to symbolize the unfamiliar morphologies displayed by stem organisms in faunas of the Burgess Shale type. They are characterized by a pair of anterior, segmented appendages, a circlet of plates around the mouth, and an elongate segmented trunk lacking true tergites with a pair of flexible lateral lobes per segment. Disarticulated body parts, such as the anterior appendages and oral circlet, had been assigned to a range of taxonomic groups--but the discovery of complete specimens from the middle Cambrian Burgess Shale showed that these disparate elements all belong to a single kind of animal. Phylogenetic analyses support a position of anomalocaridids in the arthropod stem, as a sister group to the euarthropods. The anomalocaridids were the largest animals in Cambrian communities. The youngest unequivocal examples occur in the middle Cambrian Marjum Formation of Utah but an arthropod retaining some anomalocaridid characteristics is present in the Devonian of Germany. Here we report the post-Cambrian occurrence of anomalocaridids, from the Early Ordovician (488-472 million years ago) Fezouata Biota in southeastern Morocco, including specimens larger than any in Cambrian biotas. These giant animals were an important element of some marine communities for about 30 million years longer than previously realized. The Moroccan specimens confirm the presence of a dorsal array of flexible blades attached to a transverse rachis on the trunk segments; these blades probably functioned as gills.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Roy, Peter -- Briggs, Derek E G -- England -- Nature. 2011 May 26;473(7348):510-3. doi: 10.1038/nature09920.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geology and Geophysics, Yale University, PO Box 208109, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614078" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Fossils ; Gills/anatomy & histology ; History, Ancient ; Invertebrates/*anatomy & histology/*classification/physiology ; Morocco ; Phylogeny
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  • 16
    Publication Date: 2011-11-08
    Description: Permafrost contains an estimated 1672 Pg carbon (C), an amount roughly equivalent to the total currently contained within land plants and the atmosphere. This reservoir of C is vulnerable to decomposition as rising global temperatures cause the permafrost to thaw. During thaw, trapped organic matter may become more accessible for microbial degradation and result in greenhouse gas emissions. Despite recent advances in the use of molecular tools to study permafrost microbial communities, their response to thaw remains unclear. Here we use deep metagenomic sequencing to determine the impact of thaw on microbial phylogenetic and functional genes, and relate these data to measurements of methane emissions. Metagenomics, the direct sequencing of DNA from the environment, allows the examination of whole biochemical pathways and associated processes, as opposed to individual pieces of the metabolic puzzle. Our metagenome analyses reveal that during transition from a frozen to a thawed state there are rapid shifts in many microbial, phylogenetic and functional gene abundances and pathways. After one week of incubation at 5 degrees C, permafrost metagenomes converge to be more similar to each other than while they are frozen. We find that multiple genes involved in cycling of C and nitrogen shift rapidly during thaw. We also construct the first draft genome from a complex soil metagenome, which corresponds to a novel methanogen. Methane previously accumulated in permafrost is released during thaw and subsequently consumed by methanotrophic bacteria. Together these data point towards the importance of rapid cycling of methane and nitrogen in thawing permafrost.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mackelprang, Rachel -- Waldrop, Mark P -- DeAngelis, Kristen M -- David, Maude M -- Chavarria, Krystle L -- Blazewicz, Steven J -- Rubin, Edward M -- Jansson, Janet K -- England -- Nature. 2011 Nov 6;480(7377):368-71. doi: 10.1038/nature10576.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, California State University at Northridge, Northridge, California 91330, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22056985" target="_blank"〉PubMed〈/a〉
    Keywords: Alaska ; Arctic Regions ; Bacteria/*genetics/isolation & purification/*metabolism ; Carbon/metabolism ; Carbon Cycle/genetics ; DNA/analysis/genetics ; *Freezing ; Genes, rRNA/genetics ; Metagenome/*genetics ; *Metagenomics ; Methane/metabolism ; Nitrogen/metabolism ; Nitrogen Cycle/genetics ; Oxidation-Reduction ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Soil/chemistry ; *Soil Microbiology ; *Temperature ; Time Factors
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  • 17
    Publication Date: 2011-10-25
    Description: Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0-D1-D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards beta2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an 'innate HLA sensor' domain. Second, whereas the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723390/" 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/PMC3723390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vivian, Julian P -- Duncan, Renee C -- Berry, Richard -- O'Connor, Geraldine M -- Reid, Hugh H -- Beddoe, Travis -- Gras, Stephanie -- Saunders, Philippa M -- Olshina, Maya A -- Widjaja, Jacqueline M L -- Harpur, Christopher M -- Lin, Jie -- Maloveste, Sebastien M -- Price, David A -- Lafont, Bernard A P -- McVicar, Daniel W -- Clements, Craig S -- Brooks, Andrew G -- Rossjohn, Jamie -- G0501963/Medical Research Council/United Kingdom -- ZIA AI001026-04/Intramural NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Oct 23;479(7373):401-5. doi: 10.1038/nature10517.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22020283" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites/genetics ; HLA-B Antigens/*chemistry/genetics/*immunology ; Humans ; Models, Molecular ; Mutant Proteins/chemistry/genetics/immunology ; Polymorphism, Genetic/genetics ; Protein Structure, Tertiary ; Receptors, KIR3DL1/*chemistry/genetics/*immunology ; Structure-Activity Relationship ; beta 2-Microglobulin/chemistry/immunology
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  • 18
    Publication Date: 2011-07-15
    Description: Many cellular functions involve multi-domain proteins, which are composed of structurally independent modules connected by flexible linkers. Although it is often well understood how a given domain recognizes a cognate oligonucleotide or peptide motif, the dynamic interaction of multiple domains in the recognition of these ligands remains to be characterized. Here we have studied the molecular mechanisms of the recognition of the 3'-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65) as a key early step in pre-mRNA splicing. We show that the tandem RNA recognition motif domains of U2AF65 adopt two remarkably distinct domain arrangements in the absence or presence of a strong (that is, high affinity) polypyrimidine tract. Recognition of sequence variations in the polypyrimidine tract RNA involves a population shift between these closed and open conformations. The equilibrium between the two conformations functions as a molecular rheostat that quantitatively correlates the natural variations in polypyrimidine tract nucleotide composition, length and functional strength to the efficiency to recruit U2 snRNP to the intron during spliceosome assembly. Mutations that shift the conformational equilibrium without directly affecting RNA binding modulate splicing activity accordingly. Similar mechanisms of cooperative multi-domain conformational selection may operate more generally in the recognition of degenerate nucleotide or amino acid motifs by multi-domain proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mackereth, Cameron D -- Madl, Tobias -- Bonnal, Sophie -- Simon, Bernd -- Zanier, Katia -- Gasch, Alexander -- Rybin, Vladimir -- Valcarcel, Juan -- Sattler, Michael -- England -- Nature. 2011 Jul 13;475(7356):408-11. doi: 10.1038/nature10171.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Structural Biology, Helmholtz Zentrum Munchen, Ingolstadter Landstrasse 1, 85764 Neuherberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21753750" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Base Sequence ; Humans ; Introns/genetics ; Ligands ; Models, Molecular ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Nuclear Proteins/*chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Pyrimidines/metabolism ; RNA Precursors/*genetics/*metabolism ; RNA Splice Sites/genetics ; RNA Splicing/*physiology ; RNA, Messenger/genetics/*metabolism ; Ribonucleoproteins/*chemistry/*metabolism ; Spliceosomes/chemistry/metabolism ; Substrate Specificity
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  • 19
    Publication Date: 2011-10-21
    Description: The radiation of the mammals provides a 165-million-year test case for evolutionary theories of how species occupy and then fill ecological niches. It is widely assumed that species often diverge rapidly early in their evolution, and that this is followed by a longer, drawn-out period of slower evolutionary fine-tuning as natural selection fits organisms into an increasingly occupied niche space. But recent studies have hinted that the process may not be so simple. Here we apply statistical methods that automatically detect temporal shifts in the rate of evolution through time to a comprehensive mammalian phylogeny and data set of body sizes of 3,185 extant species. Unexpectedly, the majority of mammal species, including two of the most speciose orders (Rodentia and Chiroptera), have no history of substantial and sustained increases in the rates of evolution. Instead, a subset of the mammals has experienced an explosive increase (between 10- and 52-fold) in the rate of evolution along the single branch leading to the common ancestor of their monophyletic group (for example Chiroptera), followed by a quick return to lower or background levels. The remaining species are a taxonomically diverse assemblage showing a significant, sustained increase or decrease in their rates of evolution. These results necessarily decouple morphological diversification from speciation and suggest that the processes that give rise to the morphological diversity of a class of animals are far more free to vary than previously considered. Niches do not seem to fill up, and diversity seems to arise whenever, wherever and at whatever rate it is advantageous.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venditti, Chris -- Meade, Andrew -- Pagel, Mark -- England -- Nature. 2011 Oct 19;479(7373):393-6. doi: 10.1038/nature10516.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, University of Hull, Hull HU6 7RX, UK. c.venditti@hull.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22012260" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biodiversity ; *Biological Evolution ; Body Size ; Genetic Speciation ; Mammals/anatomy & histology/classification/*physiology ; Models, Biological ; Phylogeny ; Time Factors
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  • 20
    Publication Date: 2011-01-21
    Description: The mature capsids of human immunodeficiency virus type 1 (HIV-1) and other retroviruses are fullerene shells, composed of the viral CA protein, that enclose the viral genome and facilitate its delivery into new host cells. Retroviral CA proteins contain independently folded amino (N)- and carboxy (C)-terminal domains (NTD and CTD) that are connected by a flexible linker. The NTD forms either hexameric or pentameric rings, whereas the CTD forms symmetric homodimers that connect the rings into a hexagonal lattice. We previously used a disulphide crosslinking strategy to enable isolation and crystallization of soluble HIV-1 CA hexamers. Here we use the same approach to solve the X-ray structure of the HIV-1 CA pentamer at 2.5 A resolution. Two mutant CA proteins with engineered disulphides at different positions (P17C/T19C and N21C/A22C) converged onto the same quaternary structure, indicating that the disulphide-crosslinked proteins recapitulate the structure of the native pentamer. Assembly of the quasi-equivalent hexamers and pentamers requires remarkably subtle rearrangements in subunit interactions, and appears to be controlled by an electrostatic switch that favours hexamers over pentamers. This study completes the gallery of substructures describing the components of the HIV-1 capsid and enables atomic-level modelling of the complete capsid. Rigid-body rotations around two assembly interfaces appear sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075868/" 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/PMC3075868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pornillos, Owen -- Ganser-Pornillos, Barbie K -- Yeager, Mark -- P50 GM082545/GM/NIGMS NIH HHS/ -- P50 GM082545-05/GM/NIGMS NIH HHS/ -- P50-GM082545/GM/NIGMS NIH HHS/ -- R01 GM066087/GM/NIGMS NIH HHS/ -- R01 GM066087-09/GM/NIGMS NIH HHS/ -- R01-GM066087/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jan 20;469(7330):424-7. doi: 10.1038/nature09640.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248851" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/*chemistry ; Crystallization ; Crystallography, X-Ray ; Disulfides/chemistry ; Fullerenes/chemistry ; HIV-1/*chemistry ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Rotation ; Static Electricity
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  • 21
    Publication Date: 2011-09-17
    Description: We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276836/" 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/PMC3276836/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keane, Thomas M -- Goodstadt, Leo -- Danecek, Petr -- White, Michael A -- Wong, Kim -- Yalcin, Binnaz -- Heger, Andreas -- Agam, Avigail -- Slater, Guy -- Goodson, Martin -- Furlotte, Nicholas A -- Eskin, Eleazar -- Nellaker, Christoffer -- Whitley, Helen -- Cleak, James -- Janowitz, Deborah -- Hernandez-Pliego, Polinka -- Edwards, Andrew -- Belgard, T Grant -- Oliver, Peter L -- McIntyre, Rebecca E -- Bhomra, Amarjit -- Nicod, Jerome -- Gan, Xiangchao -- Yuan, Wei -- van der Weyden, Louise -- Steward, Charles A -- Bala, Sendu -- Stalker, Jim -- Mott, Richard -- Durbin, Richard -- Jackson, Ian J -- Czechanski, Anne -- Guerra-Assuncao, Jose Afonso -- Donahue, Leah Rae -- Reinholdt, Laura G -- Payseur, Bret A -- Ponting, Chris P -- Birney, Ewan -- Flint, Jonathan -- Adams, David J -- 077192/Wellcome Trust/United Kingdom -- 079912/Wellcome Trust/United Kingdom -- 082356/Wellcome Trust/United Kingdom -- 083573/Wellcome Trust/United Kingdom -- 083573/Z/07/Z/Wellcome Trust/United Kingdom -- 085906/Wellcome Trust/United Kingdom -- 085906/Z/08/Z/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 2T15LM007359/LM/NLM NIH HHS/ -- A6997/Cancer Research UK/United Kingdom -- BB/F022697/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0800024/Medical Research Council/United Kingdom -- K25 HL080079/HL/NHLBI NIH HHS/ -- MC_U127561112/Medical Research Council/United Kingdom -- MC_U137761446/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Sep 14;477(7364):289-94. doi: 10.1038/nature10413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21921910" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Animals, Laboratory/genetics ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Genome/*genetics ; Genomics ; Mice/classification/*genetics ; Mice, Inbred C57BL/genetics ; Mice, Inbred Strains/*genetics ; *Phenotype ; Phylogeny ; Quantitative Trait Loci/genetics
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  • 22
    Publication Date: 2011-06-17
    Description: Transforming growth factor (TGF)-beta is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-beta1 requires the binding of alpha(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-beta binding proteins. Crystals of dimeric porcine proTGF-beta1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between alpha(v)beta(6) integrin and the prodomain is insufficient for TGF-beta1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-beta family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717672/" 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/PMC4717672/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shi, Minlong -- Zhu, Jianghai -- Wang, Rui -- Chen, Xing -- Mi, Lizhi -- Walz, Thomas -- Springer, Timothy A -- P01 HL103526/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 15;474(7351):343-9. doi: 10.1038/nature10152.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677751" target="_blank"〉PubMed〈/a〉
    Keywords: Activins/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Antigens, Neoplasm/chemistry/metabolism ; Camurati-Engelmann Syndrome/genetics ; Cell Line ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Integrins/chemistry/metabolism ; Latent TGF-beta Binding Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multigene Family ; Mutation/genetics ; Oligopeptides/chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, Transforming Growth Factor beta/chemistry/metabolism ; Swine ; Transforming Growth Factor beta1/biosynthesis/*chemistry/genetics/*metabolism
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  • 23
    Publication Date: 2011-07-26
    Description: Despite the enormous ecological and economic importance of coral reefs, the keystone organisms in their establishment, the scleractinian corals, increasingly face a range of anthropogenic challenges including ocean acidification and seawater temperature rise. To understand better the molecular mechanisms underlying coral biology, here we decoded the approximately 420-megabase genome of Acropora digitifera using next-generation sequencing technology. This genome contains approximately 23,700 gene models. Molecular phylogenetics indicate that the coral and the sea anemone Nematostella vectensis diverged approximately 500 million years ago, considerably earlier than the time over which modern corals are represented in the fossil record ( approximately 240 million years ago). Despite the long evolutionary history of the endosymbiosis, no evidence was found for horizontal transfer of genes from symbiont to host. However, unlike several other corals, Acropora seems to lack an enzyme essential for cysteine biosynthesis, implying dependency of this coral on its symbionts for this amino acid. Corals inhabit environments where they are frequently exposed to high levels of solar radiation, and analysis of the Acropora genome data indicates that the coral host can independently carry out de novo synthesis of mycosporine-like amino acids, which are potent ultraviolet-protective compounds. In addition, the coral innate immunity repertoire is notably more complex than that of the sea anemone, indicating that some of these genes may have roles in symbiosis or coloniality. A number of genes with putative roles in calcification were identified, and several of these are restricted to corals. The coral genome provides a platform for understanding the molecular basis of symbiosis and responses to environmental changes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinzato, Chuya -- Shoguchi, Eiichi -- Kawashima, Takeshi -- Hamada, Mayuko -- Hisata, Kanako -- Tanaka, Makiko -- Fujie, Manabu -- Fujiwara, Mayuki -- Koyanagi, Ryo -- Ikuta, Tetsuro -- Fujiyama, Asao -- Miller, David J -- Satoh, Nori -- England -- Nature. 2011 Jul 24;476(7360):320-3. doi: 10.1038/nature10249.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Marine Genomics Unit, Okinawa Institute of Science and Technology Promotion Corporation, Onna, Okinawa 904-0412, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21785439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/chemistry/*genetics/immunology/*physiology ; *Climate Change ; Coral Reefs ; Cyclohexylamines ; Cystathionine beta-Synthase/genetics ; Cysteine/biosynthesis ; DNA Damage/genetics/radiation effects ; Fossils ; Genome/*genetics ; Glycine/analogs & derivatives/biosynthesis ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary ; Sea Anemones/genetics/immunology ; Symbiosis/genetics ; Ultraviolet Rays
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  • 24
    Publication Date: 2011-04-15
    Description: Languages vary widely but not without limit. The central goal of linguistics is to describe the diversity of human languages and explain the constraints on that diversity. Generative linguists following Chomsky have claimed that linguistic diversity must be constrained by innate parameters that are set as a child learns a language. In contrast, other linguists following Greenberg have claimed that there are statistical tendencies for co-occurrence of traits reflecting universal systems biases, rather than absolute constraints or parametric variation. Here we use computational phylogenetic methods to address the nature of constraints on linguistic diversity in an evolutionary framework. First, contrary to the generative account of parameter setting, we show that the evolution of only a few word-order features of languages are strongly correlated. Second, contrary to the Greenbergian generalizations, we show that most observed functional dependencies between traits are lineage-specific rather than universal tendencies. These findings support the view that-at least with respect to word order-cultural evolution is the primary factor that determines linguistic structure, with the current state of a linguistic system shaping and constraining future states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dunn, Michael -- Greenhill, Simon J -- Levinson, Stephen C -- Gray, Russell D -- England -- Nature. 2011 May 5;473(7345):79-82. doi: 10.1038/nature09923. Epub 2011 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Psycholinguistics, Post Office Box 310, 6500 AH Nijmegen, The Netherlands. michael.dunn@mpi.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490599" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; Cultural Evolution ; Humans ; *Language ; *Linguistics ; Phylogeny
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  • 25
    Publication Date: 2011-06-17
    Description: Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-beta-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073670/" 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/PMC4073670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sievers, Stuart A -- Karanicolas, John -- Chang, Howard W -- Zhao, Anni -- Jiang, Lin -- Zirafi, Onofrio -- Stevens, Jason T -- Munch, Jan -- Baker, David -- Eisenberg, David -- P50 AG016570/AG/NIA NIH HHS/ -- R01 AG029430/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 15;475(7354):96-100. doi: 10.1038/nature10154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles, California 90095-1570, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677644" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acids/*chemistry/*pharmacology ; Amyloid/*antagonists & inhibitors/*chemistry/metabolism ; Amyloid beta-Peptides/antagonists & inhibitors/chemistry/metabolism ; Computer-Aided Design ; *Drug Design ; HIV Infections/virology ; Hydrogen Bonding ; Kinetics ; Models, Molecular ; Peptides/*chemistry/*pharmacology ; Polylysine/pharmacology ; Protein Conformation ; tau Proteins/antagonists & inhibitors
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  • 26
    Publication Date: 2011-03-04
    Description: Regulated proteolysis by ATP-dependent proteases is universal in all living cells. Bacterial ClpC, a member of the Clp/Hsp100 family of AAA+ proteins (ATPases associated with diverse cellular activities) with two nucleotide-binding domains (D1 and D2), requires the adaptor protein MecA for activation and substrate targeting. The activated, hexameric MecA-ClpC molecular machine harnesses the energy of ATP binding and hydrolysis to unfold specific substrate proteins and translocate the unfolded polypeptide to the ClpP protease for degradation. Here we report three related crystal structures: a heterodimer between MecA and the amino domain of ClpC, a heterododecamer between MecA and D2-deleted ClpC, and a hexameric complex between MecA and full-length ClpC. In conjunction with biochemical analyses, these structures reveal the organizational principles behind the hexameric MecA-ClpC complex, explain the molecular mechanisms for MecA-mediated ClpC activation and provide mechanistic insights into the function of the MecA-ClpC molecular machine. These findings have implications for related Clp/Hsp100 molecular machines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Feng -- Mei, Ziqing -- Qi, Yutao -- Yan, Chuangye -- Hu, Qi -- Wang, Jiawei -- Shi, Yigong -- England -- Nature. 2011 Mar 17;471(7338):331-5. doi: 10.1038/nature09780. Epub 2011 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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/21368759" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Endopeptidase Clp/metabolism ; Heat-Shock Proteins/*chemistry/genetics/*metabolism ; Hydrolysis ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Unfolding ; Substrate Specificity
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  • 27
    Publication Date: 2011-05-27
    Description: Alternative splicing of pre-messenger RNAs diversifies gene products in eukaryotes and is guided by factors that enable spliceosomes to recognize particular splice sites. Here we report that alternative splicing of Saccharomyces cerevisiae SRC1 pre-mRNA is promoted by the conserved ubiquitin-like protein Hub1. Structural and biochemical data show that Hub1 binds non-covalently to a conserved element termed HIND, which is present in the spliceosomal protein Snu66 in yeast and mammals, and Prp38 in plants. Hub1 binding mildly alters spliceosomal protein interactions and barely affects general splicing in S. cerevisiae. However, spliceosomes that lack Hub1, or are defective in Hub1-HIND interaction, cannot use certain non-canonical 5' splice sites and are defective in alternative SRC1 splicing. Hub1 confers alternative splicing not only when bound to HIND, but also when experimentally fused to Snu66, Prp38, or even the core splicing factor Prp8. Our study indicates a novel mechanism for splice site utilization that is guided by non-covalent modification of the spliceosome by an unconventional ubiquitin-like modifier.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587138/" 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/PMC3587138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mishra, Shravan Kumar -- Ammon, Tim -- Popowicz, Grzegorz M -- Krajewski, Marcin -- Nagel, Roland J -- Ares, Manuel Jr -- Holak, Tad A -- Jentsch, Stefan -- GM040478/GM/NIGMS NIH HHS/ -- R01 GM040478/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 May 25;474(7350):173-8. doi: 10.1038/nature10143.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614000" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Amino Acid Sequence ; Binding Sites ; Cell Line ; Gene Deletion ; *Gene Expression Regulation, Fungal ; Humans ; Ligases/deficiency/genetics/*metabolism ; Membrane Proteins/genetics ; Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/genetics ; Protein Binding ; Protein Conformation ; RNA Splice Sites/*genetics ; RNA, Fungal/*genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Ribonucleoprotein, U4-U6 Small Nuclear/deficiency/genetics ; Ribonucleoprotein, U5 Small Nuclear/deficiency/genetics ; Ribonucleoproteins, Small Nuclear/chemistry/deficiency/genetics/metabolism ; Saccharomyces cerevisiae/chemistry/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Schizosaccharomyces/chemistry/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Spliceosomes/chemistry/metabolism ; Ubiquitin-Protein Ligase Complexes/deficiency/genetics/metabolism
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  • 28
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2011 Apr 14;472(7342):136. doi: 10.1038/472136a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490629" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Evolution ; Cognition/physiology ; Cultural Evolution ; Humans ; *Language ; *Models, Theoretical ; Phylogeny
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  • 29
    Publication Date: 2011-07-08
    Description: Swi2/Snf2-type ATPases regulate genome-associated processes such as transcription, replication and repair by catalysing the disruption, assembly or remodelling of nucleosomes or other protein-DNA complexes. It has been suggested that ATP-driven motor activity along DNA disrupts target protein-DNA interactions in the remodelling reaction. However, the complex and highly specific remodelling reactions are poorly understood, mostly because of a lack of high-resolution structural information about how remodellers bind to their substrate proteins. Mot1 (modifier of transcription 1 in Saccharomyces cerevisiae, denoted BTAF1 in humans) is a Swi2/Snf2 enzyme that specifically displaces the TATA box binding protein (TBP) from the promoter DNA and regulates transcription globally by generating a highly dynamic TBP pool in the cell. As a Swi2/Snf2 enzyme that functions as a single polypeptide and interacts with a relatively simple substrate, Mot1 offers an ideal system from which to gain a better understanding of this important enzyme family. To reveal how Mot1 specifically disrupts TBP-DNA complexes, we combined crystal and electron microscopy structures of Mot1-TBP from Encephalitozoon cuniculi with biochemical studies. Here we show that Mot1 wraps around TBP and seems to act like a bottle opener: a spring-like array of 16 HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats grips the DNA-distal side of TBP via loop insertions, and the Swi2/Snf2 domain binds to upstream DNA, positioned to weaken the TBP-DNA interaction by DNA translocation. A 'latch' subsequently blocks the DNA-binding groove of TBP, acting as a chaperone to prevent DNA re-association and ensure efficient promoter clearance. This work shows how a remodelling enzyme can combine both motor and chaperone activities to achieve functional specificity using a conserved Swi2/Snf2 translocase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276066/" 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/PMC3276066/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wollmann, Petra -- Cui, Sheng -- Viswanathan, Ramya -- Berninghausen, Otto -- Wells, Melissa N -- Moldt, Manuela -- Witte, Gregor -- Butryn, Agata -- Wendler, Petra -- Beckmann, Roland -- Auble, David T -- Hopfner, Karl-Peter -- GM55763/GM/NIGMS NIH HHS/ -- R01 GM055763/GM/NIGMS NIH HHS/ -- R01 GM055763-13/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jul 6;475(7356):403-7. doi: 10.1038/nature10215.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Ludwig-Maximilians University, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734658" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallization ; Crystallography, X-Ray ; DNA/chemistry/genetics/metabolism/ultrastructure ; Encephalitozoon cuniculi/*chemistry ; Fungal Proteins/*chemistry/*metabolism/ultrastructure ; Microscopy, Electron ; Models, Biological ; Models, Molecular ; Promoter Regions, Genetic/genetics ; Protein Conformation ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Substrate Specificity ; TATA-Box Binding Protein/*chemistry/*metabolism/ultrastructure ; Transcription Factor TFIIB/chemistry/metabolism
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  • 30
    Publication Date: 2011-09-29
    Description: Transcription of the mitochondrial genome is performed by a single-subunit RNA polymerase (mtRNAP) that is distantly related to the RNAP of bacteriophage T7, the pol I family of DNA polymerases, and single-subunit RNAPs from chloroplasts. Whereas T7 RNAP can initiate transcription by itself, mtRNAP requires the factors TFAM and TFB2M for binding and melting promoter DNA. TFAM is an abundant protein that binds and bends promoter DNA 15-40 base pairs upstream of the transcription start site, and stimulates the recruitment of mtRNAP and TFB2M to the promoter. TFB2M assists mtRNAP in promoter melting and reaches the active site of mtRNAP to interact with the first base pair of the RNA-DNA hybrid. Here we report the X-ray structure of human mtRNAP at 2.5 A resolution, which reveals a T7-like catalytic carboxy-terminal domain, an amino-terminal domain that remotely resembles the T7 promoter-binding domain, a novel pentatricopeptide repeat domain, and a flexible N-terminal extension. The pentatricopeptide repeat domain sequesters an AT-rich recognition loop, which binds promoter DNA in T7 RNAP, probably explaining the need for TFAM during promoter binding. Consistent with this, substitution of a conserved arginine residue in the AT-rich recognition loop, or release of this loop by deletion of the N-terminal part of mtRNAP, had no effect on transcription. The fingers domain and the intercalating hairpin, which melts DNA in phage RNAPs, are repositioned, explaining the need for TFB2M during promoter melting. Our results provide a new venue for the mechanistic analysis of mitochondrial transcription. They also indicate how an early phage-like mtRNAP lost functions in promoter binding and melting, which were provided by initiation factors in trans during evolution, to enable mitochondrial gene regulation and the adaptation of mitochondrial function to changes in the environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ringel, Rieke -- Sologub, Marina -- Morozov, Yaroslav I -- Litonin, Dmitry -- Cramer, Patrick -- Temiakov, Dmitry -- England -- Nature. 2011 Sep 25;478(7368):269-73. doi: 10.1038/nature10435.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Department of Biochemistry, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21947009" target="_blank"〉PubMed〈/a〉
    Keywords: AT Rich Sequence/genetics ; Amino Acid Sequence ; Bacteriophage T7/enzymology ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA/chemistry/genetics/metabolism ; DNA-Directed RNA Polymerases/*chemistry/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mitochondria/*enzymology ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Denaturation ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary ; Sequence Alignment ; Templates, Genetic ; Viral Proteins/chemistry
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  • 31
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-10-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spoor, Fred -- England -- Nature. 2011 Oct 5;478(7367):44-5. doi: 10.1038/478044a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21979041" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Fossils ; Hominidae/*anatomy & histology/*classification ; Phylogeny ; Skeleton ; South Africa
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  • 32
    Publication Date: 2011-10-04
    Description: Many replication initiators form higher-order oligomers that process host replication origins to promote replisome formation. In addition to dedicated duplex-DNA-binding domains, cellular initiators possess AAA+ (ATPases associated with various cellular activities) elements that drive functions ranging from protein assembly to origin recognition. In bacteria, the AAA+ domain of the initiator DnaA has been proposed to assist in single-stranded DNA formation during origin melting. Here we show crystallographically and in solution that the ATP-dependent assembly of Aquifex aeolicus DnaA into a spiral oligomer creates a continuous surface that allows successive AAA+ domains to bind and extend single-stranded DNA segments. The mechanism of binding is unexpectedly similar to that of RecA, a homologous recombination factor, but it differs in that DnaA promotes a nucleic acid conformation that prevents pairing of a complementary strand. These findings, combined with strand-displacement assays, indicate that DnaA opens replication origins by a direct ATP-dependent stretching mechanism. Comparative studies reveal notable commonalities between the approach used by DnaA to engage DNA substrates and other, nucleic-acid-dependent, AAA+ systems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192921/" 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/PMC3192921/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duderstadt, Karl E -- Chuang, Kevin -- Berger, James M -- GM071747/GM/NIGMS NIH HHS/ -- R01 GM071747/GM/NIGMS NIH HHS/ -- R01 GM071747-06/GM/NIGMS NIH HHS/ -- T32 GM008295/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Oct 2;478(7368):209-13. doi: 10.1038/nature10455.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biophysics Graduate Group, University of California, Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964332" target="_blank"〉PubMed〈/a〉
    Keywords: AT Rich Sequence ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Bacteria/enzymology/genetics ; Bacterial Proteins/chemistry/*metabolism ; Biocatalysis ; Crystallography, X-Ray ; DNA Replication ; DNA, Bacterial/*chemistry/genetics/*metabolism ; DNA, Single-Stranded/chemistry/genetics/metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; DNA-Directed DNA Polymerase/metabolism ; Models, Molecular ; Molecular Conformation ; Multienzyme Complexes/metabolism ; *Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Rec A Recombinases/chemistry ; *Replication Origin/genetics ; Substrate Specificity
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  • 33
    Publication Date: 2011-03-11
    Description: G-protein-coupled receptors (GPCRs) comprise the largest family of membrane proteins in the human genome and mediate cellular responses to an extensive array of hormones, neurotransmitters and sensory stimuli. Although some crystal structures have been determined for GPCRs, most are for modified forms, showing little basal activity, and are bound to inverse agonists or antagonists. Consequently, these structures correspond to receptors in their inactive states. The visual pigment rhodopsin is the only GPCR for which structures exist that are thought to be in the active state. However, these structures are for the apoprotein, or opsin, form that does not contain the agonist all-trans retinal. Here we present a crystal structure at a resolution of 3 A for the constitutively active rhodopsin mutant Glu 113 Gln in complex with a peptide derived from the carboxy terminus of the alpha-subunit of the G protein transducin. The protein is in an active conformation that retains retinal in the binding pocket after photoactivation. Comparison with the structure of ground-state rhodopsin suggests how translocation of the retinal beta-ionone ring leads to a rotation of transmembrane helix 6, which is the critical conformational change on activation. A key feature of this conformational change is a reorganization of water-mediated hydrogen-bond networks between the retinal-binding pocket and three of the most conserved GPCR sequence motifs. We thus show how an agonist ligand can activate its GPCR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715716/" 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/PMC3715716/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Standfuss, Jorg -- Edwards, Patricia C -- D'Antona, Aaron -- Fransen, Maikel -- Xie, Guifu -- Oprian, Daniel D -- Schertler, Gebhard F X -- EY007965/EY/NEI NIH HHS/ -- MC_U105178937/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- R01 EY007965/EY/NEI NIH HHS/ -- England -- Nature. 2011 Mar 31;471(7340):656-60. doi: 10.1038/nature09795. Epub 2011 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21389983" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Crystallization ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Hydrogen Bonding/drug effects ; Ligands ; Models, Molecular ; Peptide Fragments/chemistry/metabolism ; Protein Conformation/drug effects ; Retinaldehyde/chemistry/metabolism/pharmacology ; Rhodopsin/*agonists/*chemistry/genetics/metabolism ; Rotation ; Transducin/chemistry/metabolism ; Water/chemistry/metabolism
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  • 34
    Publication Date: 2011-08-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buchen, Lizzie -- England -- Nature. 2011 Aug 24;476(7361):387-90. doi: 10.1038/476387a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21866135" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallization/history ; Crystallography, X-Ray ; History, 20th Century ; History, 21st Century ; Models, Molecular ; Receptors, G-Protein-Coupled/*chemistry/history/metabolism ; Signal Transduction
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  • 35
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-07-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buchen, Lizzie -- England -- Nature. 2011 Jul 19;475(7356):273-4. doi: 10.1038/475273a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21776050" target="_blank"〉PubMed〈/a〉
    Keywords: Cholera Toxin/pharmacology ; Heterotrimeric GTP-Binding Proteins/chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism ; *Signal Transduction/drug effects
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  • 36
    Publication Date: 2011-03-23
    Description: Inhibitor of kappaB (IkappaB) kinase (IKK) phosphorylates IkappaB proteins, leading to their degradation and the liberation of nuclear factor kappaB for gene transcription. Here we report the crystal structure of IKKbeta in complex with an inhibitor, at a resolution of 3.6 A. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, alpha-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix-loop-helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with IkappaBalpha that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKKbeta dimerization, but dimerization per se is not important for maintaining IKKbeta activity and instead is required for IKKbeta activation. Other IKK family members, IKKalpha, TBK1 and IKK-i, may have a similar trimodular architecture and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081413/" 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/PMC3081413/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Guozhou -- Lo, Yu-Chih -- Li, Qiubai -- Napolitano, Gennaro -- Wu, Xuefeng -- Jiang, Xuliang -- Dreano, Michel -- Karin, Michael -- Wu, Hao -- R01 AI050872/AI/NIAID NIH HHS/ -- R01 AI050872-10/AI/NIAID NIH HHS/ -- R01 AI079260/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Apr 21;472(7343):325-30. doi: 10.1038/nature09853. Epub 2011 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21423167" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Biocatalysis ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; I-kappa B Kinase/*antagonists & inhibitors/*chemistry/metabolism ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Substrate Specificity ; Ubiquitin/chemistry ; Xenopus laevis
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  • 37
    Publication Date: 2011-09-20
    Description: Dynamin is a mechanochemical GTPase that oligomerizes around the neck of clathrin-coated pits and catalyses vesicle scission in a GTP-hydrolysis-dependent manner. The molecular details of oligomerization and the mechanism of the mechanochemical coupling are currently unknown. Here we present the crystal structure of human dynamin 1 in the nucleotide-free state with a four-domain architecture comprising the GTPase domain, the bundle signalling element, the stalk and the pleckstrin homology domain. Dynamin 1 oligomerized in the crystals via the stalks, which assemble in a criss-cross fashion. The stalks further interact via conserved surfaces with the pleckstrin homology domain and the bundle signalling element of the neighbouring dynamin molecule. This intricate domain interaction rationalizes a number of disease-related mutations in dynamin 2 and suggests a structural model for the mechanochemical coupling that reconciles previous models of dynamin function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faelber, Katja -- Posor, York -- Gao, Song -- Held, Martin -- Roske, Yvette -- Schulze, Dennis -- Haucke, Volker -- Noe, Frank -- Daumke, Oliver -- England -- Nature. 2011 Sep 18;477(7366):556-60. doi: 10.1038/nature10369.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Crystallography, Max-Delbruck-Centrum for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany. katja.faelber@mdc-berlin.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21927000" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Dynamin I/*chemistry/metabolism ; Dynamin II/genetics/metabolism ; GTP Phosphohydrolases/chemistry/metabolism ; Guanosine Triphosphate/metabolism ; HeLa Cells ; Humans ; Hydrolysis ; Models, Molecular ; Molecular Dynamics Simulation ; *Nucleotides ; Protein Binding ; Protein Structure, Tertiary ; Signal Transduction ; Transferrin/metabolism
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  • 38
    Publication Date: 2011-12-20
    Description: Ion-translocating rotary ATPases serve either as ATP synthases, using energy from a transmembrane ion motive force to create the cell's supply of ATP, or as transmembrane ion pumps that are powered by ATP hydrolysis. The members of this family of enzymes each contain two rotary motors: one that couples ion translocation to rotation and one that couples rotation to ATP synthesis or hydrolysis. During ATP synthesis, ion translocation through the membrane-bound region of the complex causes rotation of a central rotor that drives conformational changes and ATP synthesis in the catalytic region of the complex. There are no structural models available for the intact membrane region of any ion-translocating rotary ATPase. Here we present a 9.7 A resolution map of the H(+)-driven ATP synthase from Thermus thermophilus obtained by electron cryomicroscopy of single particles in ice. The 600-kilodalton complex has an overall subunit composition of A(3)B(3)CDE(2)FG(2)IL(12). The membrane-bound motor consists of a ring of L subunits and the carboxy-terminal region of subunit I, which are equivalent to the c and a subunits of most other rotary ATPases, respectively. The map shows that the ring contains 12 L subunits and that the I subunit has eight transmembrane helices. The L(12) ring and I subunit have a surprisingly small contact area in the middle of the membrane, with helices from the I subunit making contacts with two different L subunits. The transmembrane helices of subunit I form bundles that could serve as half-channels across the membrane, with the first half-channel conducting protons from the periplasm to the L(12) ring and the second half-channel conducting protons from the L(12) ring to the cytoplasm. This structure therefore suggests the mechanism by which a transmembrane proton motive force is converted to rotation in rotary ATPases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lau, Wilson C Y -- Rubinstein, John L -- MOP 81294/Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Dec 18;481(7380):214-8. doi: 10.1038/nature10699.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22178924" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/metabolism ; *Cryoelectron Microscopy ; Ice ; Models, Biological ; Models, Molecular ; Protein Subunits/chemistry/metabolism ; Proton-Motive Force ; Proton-Translocating ATPases/*chemistry/metabolism/*ultrastructure ; *Protons ; Rotation ; Structure-Activity Relationship ; Thermus thermophilus/*enzymology
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  • 39
    Publication Date: 2011-11-29
    Description: The anaerobic oxidation of methane (AOM) with sulphate, an area currently generating great interest in microbiology, is accomplished by consortia of methanotrophic archaea (ANME) and sulphate-reducing bacteria. The enzyme activating methane in methanotrophic archaea has tentatively been identified as a homologue of methyl-coenzyme M reductase (MCR) that catalyses the methane-forming step in methanogenic archaea. Here we report an X-ray structure of the 280 kDa heterohexameric ANME-1 MCR complex. It was crystallized uniquely from a protein ensemble purified from consortia of microorganisms collected with a submersible from a Black Sea mat catalysing AOM with sulphate. Crystals grown from the heterogeneous sample diffract to 2.1 A resolution and consist of a single ANME-1 MCR population, demonstrating the strong selective power of crystallization. The structure revealed ANME-1 MCR in complex with coenzyme M and coenzyme B, indicating the same substrates for MCR from methanotrophic and methanogenic archaea. Differences between the highly similar structures of ANME-1 MCR and methanogenic MCR include a F(430) modification, a cysteine-rich patch and an altered post-translational amino acid modification pattern, which may tune the enzymes for their functions in different biological contexts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shima, Seigo -- Krueger, Martin -- Weinert, Tobias -- Demmer, Ulrike -- Kahnt, Jorg -- Thauer, Rudolf K -- Ermler, Ulrich -- England -- Nature. 2011 Nov 27;481(7379):98-101. doi: 10.1038/nature10663.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Terrestrial Microbiology, Karl-Frisch-Strasse 10, D-35043 Marburg, Germany. shima@mpi-marburg.mpg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22121022" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; Archaea/*enzymology/isolation & purification/metabolism ; *Biocatalysis ; Black Sea ; Catalytic Domain ; Coenzymes/chemistry/metabolism ; Crystallography, X-Ray ; Cysteine/metabolism ; Expeditions ; Methane/*metabolism ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases/*chemistry/*metabolism ; Protein Conformation ; Seawater/*microbiology ; Ships ; Sulfates/metabolism
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  • 40
    Publication Date: 2011-11-29
    Description: Most retroviruses require translational recoding of a viral messenger RNA stop codon to maintain a precise ratio of structural (Gag) and enzymatic (Pol) proteins during virus assembly. Pol is expressed exclusively as a Gag-Pol fusion either by ribosomal frameshifting or by read-through of the gag stop codon. Both of these mechanisms occur infrequently and only affect 5-10% of translating ribosomes, allowing the virus to maintain the critical Gag to Gag-Pol ratio. Although it is understood that the frequency of the recoding event is regulated by cis RNA motifs, no mechanistic explanation is currently available for how the critical protein ratio is maintained. Here we present the NMR structure of the murine leukaemia virus recoding signal and show that a protonation-dependent switch occurs to induce the active conformation. The equilibrium is such that at physiological pH the active, read-through permissive conformation is populated at approximately 6%: a level that correlates with in vivo protein quantities. The RNA functions by a highly sensitive, chemo-mechanical coupling tuned to ensure an optimal read-through frequency. Similar observations for a frameshifting signal indicate that this novel equilibrium-based mechanism may have a general role in translational recoding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582340/" 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/PMC3582340/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Houck-Loomis, Brian -- Durney, Michael A -- Salguero, Carolina -- Shankar, Neelaabh -- Nagle, Julia M -- Goff, Stephen P -- D'Souza, Victoria M -- R37 CA030488/CA/NCI NIH HHS/ -- R37 CA30488/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Nov 27;480(7378):561-4. doi: 10.1038/nature10657.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, 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/22121021" target="_blank"〉PubMed〈/a〉
    Keywords: *Gene Expression Regulation, Viral ; *Genes, Switch ; Leukemia Virus, Murine/genetics/*physiology ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA, Viral/*metabolism
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  • 41
    Publication Date: 2011-09-20
    Description: Dynamin-related proteins (DRPs) are multi-domain GTPases that function via oligomerization and GTP-dependent conformational changes to play central roles in regulating membrane structure across phylogenetic kingdoms. How DRPs harness self-assembly and GTP-dependent conformational changes to remodel membranes is not understood. Here we present the crystal structure of an assembly-deficient mammalian endocytic DRP, dynamin 1, lacking the proline-rich domain, in its nucleotide-free state. The dynamin 1 monomer is an extended structure with the GTPase domain and bundle signalling element positioned on top of a long helical stalk with the pleckstrin homology domain flexibly attached on its opposing end. Dynamin 1 dimer and higher order dimer multimers form via interfaces located in the stalk. Analysis of these interfaces provides insight into DRP family member specificity and regulation and provides a framework for understanding the biogenesis of higher order DRP structures and the mechanism of DRP-mediated membrane scission events.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075756/" 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/PMC4075756/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ford, Marijn G J -- Jenni, Simon -- Nunnari, Jodi -- DRG-2004-09/Howard Hughes Medical Institute/ -- R01 GM062942/GM/NIGMS NIH HHS/ -- R01 GM097432/GM/NIGMS NIH HHS/ -- R01GM062942S1/GM/NIGMS NIH HHS/ -- R01GM097432/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Sep 18;477(7366):561-6. doi: 10.1038/nature10441.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, University of California, Davis, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21927001" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Crystallization ; Crystallography, X-Ray ; Dynamin I/*chemistry/genetics/metabolism ; Guanosine Triphosphate/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Nucleotides ; Protein Binding ; Protein Conformation ; Protein Multimerization/genetics ; Protein Structure, Tertiary/genetics ; Rats
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  • 42
    Publication Date: 2011-10-28
    Description: Oxygen-containing mononuclear iron species--iron(III)-peroxo, iron(III)-hydroperoxo and iron(IV)-oxo--are key intermediates in the catalytic activation of dioxygen by iron-containing metalloenzymes. It has been difficult to generate synthetic analogues of these three active iron-oxygen species in identical host complexes, which is necessary to elucidate changes to the structure of the iron centre during catalysis and the factors that control their chemical reactivities with substrates. Here we report the high-resolution crystal structure of a mononuclear non-haem side-on iron(III)-peroxo complex, [Fe(III)(TMC)(OO)](+). We also report a series of chemical reactions in which this iron(III)-peroxo complex is cleanly converted to the iron(III)-hydroperoxo complex, [Fe(III)(TMC)(OOH)](2+), via a short-lived intermediate on protonation. This iron(III)-hydroperoxo complex then cleanly converts to the ferryl complex, [Fe(IV)(TMC)(O)](2+), via homolytic O-O bond cleavage of the iron(III)-hydroperoxo species. All three of these iron species--the three most biologically relevant iron-oxygen intermediates--have been spectroscopically characterized; we note that they have been obtained using a simple macrocyclic ligand. We have performed relative reactivity studies on these three iron species which reveal that the iron(III)-hydroperoxo complex is the most reactive of the three in the deformylation of aldehydes and that it has a similar reactivity to the iron(IV)-oxo complex in C-H bond activation of alkylaromatics. These reactivity results demonstrate that iron(III)-hydroperoxo species are viable oxidants in both nucleophilic and electrophilic reactions by iron-containing enzymes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306242/" 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/PMC3306242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Jaeheung -- Jeon, Sujin -- Wilson, Samuel A -- Liu, Lei V -- Kang, Eun A -- Braymer, Joseph J -- Lim, Mi Hee -- Hedman, Britt -- Hodgson, Keith O -- Valentine, Joan Selverstone -- Solomon, Edward I -- Nam, Wonwoo -- 5P41RR001209/RR/NCRR NIH HHS/ -- GM 40392/GM/NIGMS NIH HHS/ -- P41 RR001209/RR/NCRR NIH HHS/ -- P41 RR001209-31/RR/NCRR NIH HHS/ -- R01 GM040392/GM/NIGMS NIH HHS/ -- R01 GM040392-25/GM/NIGMS NIH HHS/ -- RR-001209/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Oct 26;478(7370):502-5. doi: 10.1038/nature10535.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22031443" target="_blank"〉PubMed〈/a〉
    Keywords: Aldehydes/metabolism ; Crystallography, X-Ray ; Enzymes/chemistry/metabolism ; Hydrogen Peroxide/*chemistry/metabolism ; Iron/*chemistry/metabolism ; Ligands ; Models, Molecular ; Nonheme Iron Proteins/chemistry/metabolism ; Oxygen/chemistry/metabolism
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  • 43
    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" 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/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
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  • 44
    Publication Date: 2011-02-05
    Description: X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals ( approximately 200 nm to 2 mum in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429598/" 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/PMC3429598/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Henry N -- Fromme, Petra -- Barty, Anton -- White, Thomas A -- Kirian, Richard A -- Aquila, Andrew -- Hunter, Mark S -- Schulz, Joachim -- DePonte, Daniel P -- Weierstall, Uwe -- Doak, R Bruce -- Maia, Filipe R N C -- Martin, Andrew V -- Schlichting, Ilme -- Lomb, Lukas -- Coppola, Nicola -- Shoeman, Robert L -- Epp, Sascha W -- Hartmann, Robert -- Rolles, Daniel -- Rudenko, Artem -- Foucar, Lutz -- Kimmel, Nils -- Weidenspointner, Georg -- Holl, Peter -- Liang, Mengning -- Barthelmess, Miriam -- Caleman, Carl -- Boutet, Sebastien -- Bogan, Michael J -- Krzywinski, Jacek -- Bostedt, Christoph -- Bajt, Sasa -- Gumprecht, Lars -- Rudek, Benedikt -- Erk, Benjamin -- Schmidt, Carlo -- Homke, Andre -- Reich, Christian -- Pietschner, Daniel -- Struder, Lothar -- Hauser, Gunter -- Gorke, Hubert -- Ullrich, Joachim -- Herrmann, Sven -- Schaller, Gerhard -- Schopper, Florian -- Soltau, Heike -- Kuhnel, Kai-Uwe -- Messerschmidt, Marc -- Bozek, John D -- Hau-Riege, Stefan P -- Frank, Matthias -- Hampton, Christina Y -- Sierra, Raymond G -- Starodub, Dmitri -- Williams, Garth J -- Hajdu, Janos -- Timneanu, Nicusor -- Seibert, M Marvin -- Andreasson, Jakob -- Rocker, Andrea -- Jonsson, Olof -- Svenda, Martin -- Stern, Stephan -- Nass, Karol -- Andritschke, Robert -- Schroter, Claus-Dieter -- Krasniqi, Faton -- Bott, Mario -- Schmidt, Kevin E -- Wang, Xiaoyu -- Grotjohann, Ingo -- Holton, James M -- Barends, Thomas R M -- Neutze, Richard -- Marchesini, Stefano -- Fromme, Raimund -- Schorb, Sebastian -- Rupp, Daniela -- Adolph, Marcus -- Gorkhover, Tais -- Andersson, Inger -- Hirsemann, Helmut -- Potdevin, Guillaume -- Graafsma, Heinz -- Nilsson, Bjorn -- Spence, John C H -- 1R01GM095583-01/GM/NIGMS NIH HHS/ -- 1U54GM094625-01/GM/NIGMS NIH HHS/ -- R01 GM095583/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Feb 3;470(7332):73-7. doi: 10.1038/nature09750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany. henry.chapman@desy.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293373" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray/instrumentation/*methods ; Lasers ; Models, Molecular ; Nanoparticles/*chemistry ; Nanotechnology/instrumentation/*methods ; Photosystem I Protein Complex/*chemistry ; Protein Conformation ; Time Factors ; X-Rays
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  • 45
    Publication Date: 2011-04-22
    Description: Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728647/" 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/PMC3728647/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arumugam, Manimozhiyan -- Raes, Jeroen -- Pelletier, Eric -- Le Paslier, Denis -- Yamada, Takuji -- Mende, Daniel R -- Fernandes, Gabriel R -- Tap, Julien -- Bruls, Thomas -- Batto, Jean-Michel -- Bertalan, Marcelo -- Borruel, Natalia -- Casellas, Francesc -- Fernandez, Leyden -- Gautier, Laurent -- Hansen, Torben -- Hattori, Masahira -- Hayashi, Tetsuya -- Kleerebezem, Michiel -- Kurokawa, Ken -- Leclerc, Marion -- Levenez, Florence -- Manichanh, Chaysavanh -- Nielsen, H Bjorn -- Nielsen, Trine -- Pons, Nicolas -- Poulain, Julie -- Qin, Junjie -- Sicheritz-Ponten, Thomas -- Tims, Sebastian -- Torrents, David -- Ugarte, Edgardo -- Zoetendal, Erwin G -- Wang, Jun -- Guarner, Francisco -- Pedersen, Oluf -- de Vos, Willem M -- Brunak, Soren -- Dore, Joel -- MetaHIT Consortium -- Antolin, Maria -- Artiguenave, Francois -- Blottiere, Herve M -- Almeida, Mathieu -- Brechot, Christian -- Cara, Carlos -- Chervaux, Christian -- Cultrone, Antonella -- Delorme, Christine -- Denariaz, Gerard -- Dervyn, Rozenn -- Foerstner, Konrad U -- Friss, Carsten -- van de Guchte, Maarten -- Guedon, Eric -- Haimet, Florence -- Huber, Wolfgang -- van Hylckama-Vlieg, Johan -- Jamet, Alexandre -- Juste, Catherine -- Kaci, Ghalia -- Knol, Jan -- Lakhdari, Omar -- Layec, Severine -- Le Roux, Karine -- Maguin, Emmanuelle -- Merieux, Alexandre -- Melo Minardi, Raquel -- M'rini, Christine -- Muller, Jean -- Oozeer, Raish -- Parkhill, Julian -- Renault, Pierre -- Rescigno, Maria -- Sanchez, Nicolas -- Sunagawa, Shinichi -- Torrejon, Antonio -- Turner, Keith -- Vandemeulebrouck, Gaetana -- Varela, Encarna -- Winogradsky, Yohanan -- Zeller, Georg -- Weissenbach, Jean -- Ehrlich, S Dusko -- Bork, Peer -- 076964/Wellcome Trust/United Kingdom -- 082372/Wellcome Trust/United Kingdom -- England -- Nature. 2011 May 12;473(7346):174-80. doi: 10.1038/nature09944. Epub 2011 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21508958" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*classification/genetics ; Bacterial Typing Techniques ; Biodiversity ; Biomarkers/analysis ; Europe ; Feces/microbiology ; Female ; Humans ; Intestines/*microbiology ; Male ; *Metagenome ; Metagenomics ; Phylogeny
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  • 46
    Publication Date: 2011-03-25
    Description: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kappaB signalling was indicated by mutations in 11 members of the NF-kappaB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560292/" 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/PMC3560292/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Michael A -- Lawrence, Michael S -- Keats, Jonathan J -- Cibulskis, Kristian -- Sougnez, Carrie -- Schinzel, Anna C -- Harview, Christina L -- Brunet, Jean-Philippe -- Ahmann, Gregory J -- Adli, Mazhar -- Anderson, Kenneth C -- Ardlie, Kristin G -- Auclair, Daniel -- Baker, Angela -- Bergsagel, P Leif -- Bernstein, Bradley E -- Drier, Yotam -- Fonseca, Rafael -- Gabriel, Stacey B -- Hofmeister, Craig C -- Jagannath, Sundar -- Jakubowiak, Andrzej J -- Krishnan, Amrita -- Levy, Joan -- Liefeld, Ted -- Lonial, Sagar -- Mahan, Scott -- Mfuko, Bunmi -- Monti, Stefano -- Perkins, Louise M -- Onofrio, Robb -- Pugh, Trevor J -- Rajkumar, S Vincent -- Ramos, Alex H -- Siegel, David S -- Sivachenko, Andrey -- Stewart, A Keith -- Trudel, Suzanne -- Vij, Ravi -- Voet, Douglas -- Winckler, Wendy -- Zimmerman, Todd -- Carpten, John -- Trent, Jeff -- Hahn, William C -- Garraway, Levi A -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- K12 CA133250/CA/NCI NIH HHS/ -- R01 AG020686/AG/NIA NIH HHS/ -- R01 AG020686-07/AG/NIA NIH HHS/ -- R01 CA133115/CA/NCI NIH HHS/ -- R01 CA133115-04/CA/NCI NIH HHS/ -- R01 CA133966/CA/NCI NIH HHS/ -- R01 CA133966-03/CA/NCI NIH HHS/ -- England -- Nature. 2011 Mar 24;471(7339):467-72. doi: 10.1038/nature09837.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02412, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430775" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Blood Coagulation/genetics ; CpG Islands/genetics ; DNA Mutational Analysis ; DNA Repair/genetics ; Exons/genetics ; Exosome Multienzyme Ribonuclease Complex ; Genome, Human/*genetics ; Genomics ; Histones/metabolism ; Homeodomain Proteins/genetics ; Homeostasis/genetics ; Humans ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Multiple Myeloma/drug therapy/enzymology/*genetics/metabolism ; Mutation/*genetics ; NF-kappa B/metabolism ; Oncogenes/genetics ; Open Reading Frames/genetics ; Protein Biosynthesis/genetics ; Protein Conformation ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/metabolism ; RNA Processing, Post-Transcriptional/genetics ; Ribonucleases/chemistry/genetics ; Signal Transduction/genetics ; Transcription, Genetic/genetics
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  • 47
    Publication Date: 2011-01-21
    Description: General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (gamma-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nury, Hugues -- Van Renterghem, Catherine -- Weng, Yun -- Tran, Alphonso -- Baaden, Marc -- Dufresne, Virginie -- Changeux, Jean-Pierre -- Sonner, James M -- Delarue, Marc -- Corringer, Pierre-Jean -- R01 GM069379/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jan 20;469(7330):428-31. doi: 10.1038/nature09647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Groupe Recepteurs-Canaux, F-75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248852" target="_blank"〉PubMed〈/a〉
    Keywords: Anesthetics, General/*chemistry/*metabolism ; Binding Sites/genetics ; Crystallography, X-Ray ; Cyanobacteria/*chemistry ; Electrophysiological Phenomena ; Isoflurane/*analogs & derivatives/chemistry/metabolism ; Ligand-Gated Ion Channels/*chemistry/genetics/*metabolism ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Mutant Proteins/chemistry/genetics/metabolism ; Propofol/*chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protons
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  • 48
    Publication Date: 2011-10-11
    Description: Enzymes catalyse specific reactions and are essential for maintaining life. Although some are referred to as being bifunctional, they consist of either two distinct catalytic domains or a single domain that displays promiscuous substrate specificity. Thus, one enzyme active site is generally responsible for one biochemical reaction. In contrast to this conventional concept, archaeal fructose-1,6-bisphosphate (FBP) aldolase/phosphatase (FBPA/P) consists of a single catalytic domain, but catalyses two chemically distinct reactions of gluconeogenesis: (1) the reversible aldol condensation of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA3P) to FBP; (2) the dephosphorylation of FBP to fructose-6-phosphate (F6P). Thus, FBPA/P is fundamentally different from ordinary enzymes whose active sites are responsible for a specific reaction. However, the molecular mechanism by which FBPA/P achieves its unusual bifunctionality remains unknown. Here we report the crystal structure of FBPA/P at 1.5-A resolution in the aldolase form, where a critical lysine residue forms a Schiff base with DHAP. A structural comparison of the aldolase form with a previously determined phosphatase form revealed a dramatic conformational change in the active site, demonstrating that FBPA/P metamorphoses its active-site architecture to exhibit dual activities. Thus, our findings expand the conventional concept that one enzyme catalyses one biochemical reaction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fushinobu, Shinya -- Nishimasu, Hiroshi -- Hattori, Daiki -- Song, Hyun-Jin -- Wakagi, Takayoshi -- England -- Nature. 2011 Oct 9;478(7370):538-41. doi: 10.1038/nature10457.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21983966" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Dihydroxyacetone Phosphate/metabolism ; Fructose-Bisphosphate Aldolase/*chemistry/*metabolism ; Fructosediphosphates/metabolism ; Gluconeogenesis ; Glyceraldehyde 3-Phosphate/metabolism ; Lysine/metabolism ; Magnesium/metabolism ; Models, Molecular ; Phosphoric Monoester Hydrolases/*chemistry/*metabolism ; Phosphorylation ; Protein Conformation ; Schiff Bases/chemistry/metabolism ; Sulfolobus/*enzymology
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  • 49
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    Nature Publishing Group (NPG)
    Publication Date: 2011-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narbonne, Guy M -- England -- Nature. 2011 Feb 17;470(7334):339-40. doi: 10.1038/470339a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331031" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; *Biota ; Body Size ; China ; Eukaryota/*classification/isolation & purification ; *Fossils ; Phylogeny
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  • 50
    Publication Date: 2011-01-29
    Description: 'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060778/" 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/PMC3060778/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Locke, Devin P -- Hillier, LaDeana W -- Warren, Wesley C -- Worley, Kim C -- Nazareth, Lynne V -- Muzny, Donna M -- Yang, Shiaw-Pyng -- Wang, Zhengyuan -- Chinwalla, Asif T -- Minx, Pat -- Mitreva, Makedonka -- Cook, Lisa -- Delehaunty, Kim D -- Fronick, Catrina -- Schmidt, Heather -- Fulton, Lucinda A -- Fulton, Robert S -- Nelson, Joanne O -- Magrini, Vincent -- Pohl, Craig -- Graves, Tina A -- Markovic, Chris -- Cree, Andy -- Dinh, Huyen H -- Hume, Jennifer -- Kovar, Christie L -- Fowler, Gerald R -- Lunter, Gerton -- Meader, Stephen -- Heger, Andreas -- Ponting, Chris P -- Marques-Bonet, Tomas -- Alkan, Can -- Chen, Lin -- Cheng, Ze -- Kidd, Jeffrey M -- Eichler, Evan E -- White, Simon -- Searle, Stephen -- Vilella, Albert J -- Chen, Yuan -- Flicek, Paul -- Ma, Jian -- Raney, Brian -- Suh, Bernard -- Burhans, Richard -- Herrero, Javier -- Haussler, David -- Faria, Rui -- Fernando, Olga -- Darre, Fleur -- Farre, Domenec -- Gazave, Elodie -- Oliva, Meritxell -- Navarro, Arcadi -- Roberto, Roberta -- Capozzi, Oronzo -- Archidiacono, Nicoletta -- Della Valle, Giuliano -- Purgato, Stefania -- Rocchi, Mariano -- Konkel, Miriam K -- Walker, Jerilyn A -- Ullmer, Brygg -- Batzer, Mark A -- Smit, Arian F A -- Hubley, Robert -- Casola, Claudio -- Schrider, Daniel R -- Hahn, Matthew W -- Quesada, Victor -- Puente, Xose S -- Ordonez, Gonzalo R -- Lopez-Otin, Carlos -- Vinar, Tomas -- Brejova, Brona -- Ratan, Aakrosh -- Harris, Robert S -- Miller, Webb -- Kosiol, Carolin -- Lawson, Heather A -- Taliwal, Vikas -- Martins, Andre L -- Siepel, Adam -- Roychoudhury, Arindam -- Ma, Xin -- Degenhardt, Jeremiah -- Bustamante, Carlos D -- Gutenkunst, Ryan N -- Mailund, Thomas -- Dutheil, Julien Y -- Hobolth, Asger -- Schierup, Mikkel H -- Ryder, Oliver A -- Yoshinaga, Yuko -- de Jong, Pieter J -- Weinstock, George M -- Rogers, Jeffrey -- Mardis, Elaine R -- Gibbs, Richard A -- Wilson, Richard K -- G0501331/Medical Research Council/United Kingdom -- HG002238/HG/NHGRI NIH HHS/ -- HG002385/HG/NHGRI NIH HHS/ -- MC_U137761446/Medical Research Council/United Kingdom -- P01 AG022064/AG/NIA NIH HHS/ -- R01 GM059290/GM/NIGMS NIH HHS/ -- R01 GM59290/GM/NIGMS NIH HHS/ -- R01 HG002939/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003079-08/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Jan 27;469(7331):529-33. doi: 10.1038/nature09687.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Genome Center at Washington University, Washington University School of Medicine, 4444 Forest Park Avenue, Saint Louis, Missouri 63108, USA. dlocke@wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21270892" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Centromere/genetics ; Cerebrosides/metabolism ; Chromosomes ; Evolution, Molecular ; Female ; Gene Rearrangement/genetics ; Genetic Speciation ; *Genetic Variation ; Genetics, Population ; Genome/*genetics ; Humans ; Male ; Phylogeny ; Pongo abelii/*genetics ; Pongo pygmaeus/*genetics ; Population Density ; Population Dynamics ; Species Specificity
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  • 51
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-09-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lok, Corie -- England -- Nature. 2011 Sep 15;477(7364):359-61.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21928542" target="_blank"〉PubMed〈/a〉
    Keywords: Computer Graphics/instrumentation/utilization ; *Medical Illustration/education ; Models, Molecular ; Molecular Biology/manpower/*methods ; Motion Pictures as Topic/instrumentation/utilization ; Research Personnel/education ; Software
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  • 52
    Publication Date: 2011-03-18
    Description: The centromere is a unique chromosomal locus that ensures accurate segregation of chromosomes during cell division by directing the assembly of a multiprotein complex, the kinetochore. The centromere is marked by a conserved variant of conventional histone H3 termed CenH3 or CENP-A (ref. 2). A conserved motif of CenH3, the CATD, defined by loop 1 and helix 2 of the histone fold, is necessary and sufficient for specifying centromere functions of CenH3 (refs 3, 4). The structural basis of this specification is of particular interest. Yeast Scm3 and human HJURP are conserved non-histone proteins that interact physically with the (CenH3-H4)(2) heterotetramer and are required for the deposition of CenH3 at centromeres in vivo. Here we have elucidated the structural basis for recognition of budding yeast (Saccharomyces cerevisiae) CenH3 (called Cse4) by Scm3. We solved the structure of the Cse4-binding domain (CBD) of Scm3 in complex with Cse4 and H4 in a single chain model. An alpha-helix and an irregular loop at the conserved amino terminus and a shorter alpha-helix at the carboxy terminus of Scm3(CBD) wraps around the Cse4-H4 dimer. Four Cse4-specific residues in the N-terminal region of helix 2 are sufficient for specific recognition by conserved and functionally important residues in the N-terminal helix of Scm3 through formation of a hydrophobic cluster. Scm3(CBD) induces major conformational changes and sterically occludes DNA-binding sites in the structure of Cse4 and H4. These findings have implications for the assembly and architecture of the centromeric nucleosome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077455/" 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/PMC3077455/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Zheng -- Feng, Hanqiao -- Zhou, Bing-Rui -- Ghirlando, Rodolfo -- Hu, Kaifeng -- Zwolak, Adam -- Miller Jenkins, Lisa M -- Xiao, Hua -- Tjandra, Nico -- Wu, Carl -- Bai, Yawen -- Z01 BC010808-01/Intramural NIH HHS/ -- England -- Nature. 2011 Apr 14;472(7342):234-7. doi: 10.1038/nature09854. Epub 2011 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21412236" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Autoantigens/chemistry/metabolism ; Binding Sites ; Centromere/*chemistry/metabolism ; Chromosomal Proteins, Non-Histone/*chemistry/*metabolism ; Conserved Sequence ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/*metabolism ; Histones/chemistry/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Chaperones/chemistry/metabolism ; Molecular Sequence Data ; Nuclear Magnetic Resonance, Biomolecular ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Conformation ; *Saccharomyces cerevisiae/cytology/metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism
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  • 53
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Honig, Barry -- Rohs, Remo -- England -- Nature. 2011 Feb 24;470(7335):472-3. doi: 10.1038/470472a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350476" target="_blank"〉PubMed〈/a〉
    Keywords: *Base Pairing ; DNA/*chemistry/metabolism ; DNA-Binding Proteins/metabolism ; Hydrogen Bonding ; Magnetic Resonance Spectroscopy ; Models, Molecular
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  • 54
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-07-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lerdau, Manuel -- Wickham, Jacob D -- England -- Nature. 2011 Jul 6;475(7354):36-7. doi: 10.1038/475036d.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734690" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Beetles/physiology ; China ; Ecology/*methods ; Food Chain ; *Introduced Species/statistics & numerical data ; North America ; Phylogeny ; Reproduction/physiology ; Risk Factors ; Trees/physiology
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  • 55
    Publication Date: 2011-04-12
    Description: Whole-genome duplication (WGD), or polyploidy, followed by gene loss and diploidization has long been recognized as an important evolutionary force in animals, fungi and other organisms, especially plants. The success of angiosperms has been attributed, in part, to innovations associated with gene or whole-genome duplications, but evidence for proposed ancient genome duplications pre-dating the divergence of monocots and eudicots remains equivocal in analyses of conserved gene order. Here we use comprehensive phylogenomic analyses of sequenced plant genomes and more than 12.6 million new expressed-sequence-tag sequences from phylogenetically pivotal lineages to elucidate two groups of ancient gene duplications-one in the common ancestor of extant seed plants and the other in the common ancestor of extant angiosperms. Gene duplication events were intensely concentrated around 319 and 192 million years ago, implicating two WGDs in ancestral lineages shortly before the diversification of extant seed plants and extant angiosperms, respectively. Significantly, these ancestral WGDs resulted in the diversification of regulatory genes important to seed and flower development, suggesting that they were involved in major innovations that ultimately contributed to the rise and eventual dominance of seed plants and angiosperms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiao, Yuannian -- Wickett, Norman J -- Ayyampalayam, Saravanaraj -- Chanderbali, Andre S -- Landherr, Lena -- Ralph, Paula E -- Tomsho, Lynn P -- Hu, Yi -- Liang, Haiying -- Soltis, Pamela S -- Soltis, Douglas E -- Clifton, Sandra W -- Schlarbaum, Scott E -- Schuster, Stephan C -- Ma, Hong -- Leebens-Mack, Jim -- dePamphilis, Claude W -- England -- Nature. 2011 May 5;473(7345):97-100. doi: 10.1038/nature09916. Epub 2011 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Intercollege Graduate Degree Program in Plant Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21478875" target="_blank"〉PubMed〈/a〉
    Keywords: Angiosperms/*classification/*genetics ; *Evolution, Molecular ; Genome, Plant/*genetics ; Genomics ; Phylogeny ; *Polyploidy
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  • 56
    Publication Date: 2011-06-21
    Description: Mitochondria from diverse organisms are capable of transporting large amounts of Ca(2+) via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter. Although the uniporter's biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand-containing protein that serves as a putative regulator of the uniporter. Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call 'mitochondrial calcium uniporter' (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca(2+) uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca(2+) uniporter.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486726/" 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/PMC3486726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baughman, Joshua M -- Perocchi, Fabiana -- Girgis, Hany S -- Plovanich, Molly -- Belcher-Timme, Casey A -- Sancak, Yasemin -- Bao, X Robert -- Strittmatter, Laura -- Goldberger, Olga -- Bogorad, Roman L -- Koteliansky, Victor -- Mootha, Vamsi K -- DK080261/DK/NIDDK NIH HHS/ -- GM0077465/GM/NIGMS NIH HHS/ -- R01 GM077465/GM/NIGMS NIH HHS/ -- R01 GM077465-01A1/GM/NIGMS NIH HHS/ -- R24 DK080261/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jun 19;476(7360):341-5. doi: 10.1038/nature10234.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21685886" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Calcium/metabolism ; Calcium Channels/*chemistry/genetics/*metabolism ; *Genomics ; HEK293 Cells ; HeLa Cells ; Humans ; Ion Transport ; Mice ; Mitochondria, Liver/metabolism ; Mitochondrial Membranes/chemistry/metabolism ; Molecular Sequence Data ; Mutant Proteins/genetics/metabolism ; Phylogeny ; Protein Structure, Quaternary ; Protein Structure, Tertiary
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  • 57
    Publication Date: 2011-11-15
    Description: Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways. Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245779/" 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/PMC3245779/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crosnier, Cecile -- Bustamante, Leyla Y -- Bartholdson, S Josefin -- Bei, Amy K -- Theron, Michel -- Uchikawa, Makoto -- Mboup, Souleymane -- Ndir, Omar -- Kwiatkowski, Dominic P -- Duraisingh, Manoj T -- Rayner, Julian C -- Wright, Gavin J -- 077108/Wellcome Trust/United Kingdom -- 089084/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 2T32 AI007535-12/AI/NIAID NIH HHS/ -- G19/9/Medical Research Council/United Kingdom -- R01 AI057919/AI/NIAID NIH HHS/ -- R01 AI057919-05/AI/NIAID NIH HHS/ -- R01AI057919/AI/NIAID NIH HHS/ -- R36 CK000119-01/CK/NCEZID CDC HHS/ -- England -- Nature. 2011 Nov 9;480(7378):534-7. doi: 10.1038/nature10606.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080952" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, CD147/chemistry/genetics/*metabolism ; Erythrocytes/metabolism/*parasitology ; Gene Knockdown Techniques ; *Host-Parasite Interactions ; Humans ; Models, Molecular ; Plasmodium falciparum/*physiology ; Protein Structure, Tertiary
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  • 58
    Publication Date: 2011-11-08
    Description: SAMHD1, an analogue of the murine interferon (IFN)-gamma-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutieres syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-alpha. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldstone, David C -- Ennis-Adeniran, Valerie -- Hedden, Joseph J -- Groom, Harriet C T -- Rice, Gillian I -- Christodoulou, Evangelos -- Walker, Philip A -- Kelly, Geoff -- Haire, Lesley F -- Yap, Melvyn W -- de Carvalho, Luiz Pedro S -- Stoye, Jonathan P -- Crow, Yanick J -- Taylor, Ian A -- Webb, Michelle -- MC_U117512710/Medical Research Council/United Kingdom -- MC_U117533887/Medical Research Council/United Kingdom -- MC_U117565647/Medical Research Council/United Kingdom -- MC_UP_A253_1111/Medical Research Council/United Kingdom -- U117512710/Medical Research Council/United Kingdom -- U117565647/Medical Research Council/United Kingdom -- England -- Nature. 2011 Nov 6;480(7377):379-82. doi: 10.1038/nature10623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Structure, MRC National Institute for Medical Research, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22056990" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Dendritic Cells/metabolism/virology ; Deoxyadenine Nucleotides/metabolism ; Deoxycytosine Nucleotides/metabolism ; Deoxyguanine Nucleotides/metabolism ; HIV-1/*physiology ; Humans ; Hydrolysis ; Models, Biological ; Models, Molecular ; Monomeric GTP-Binding Proteins/*chemistry/genetics/*metabolism ; Myeloid Cells/virology ; Nucleoside-Triphosphatase/*chemistry/genetics/*metabolism ; Protein Structure, Tertiary ; Reverse Transcription ; Thymine Nucleotides/metabolism ; Viral Regulatory and Accessory Proteins/metabolism ; Virus Replication
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  • 59
    Publication Date: 2011-07-12
    Description: Voltage-gated sodium (Na(V)) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na(+) channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 A resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4-S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, approximately 4.6 A wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na(+) selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266868/" 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/PMC3266868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payandeh, Jian -- Scheuer, Todd -- Zheng, Ning -- Catterall, William A -- R01 NS015751/NS/NINDS NIH HHS/ -- R01 NS015751-24/NS/NINDS NIH HHS/ -- R01 NS15751/NS/NINDS NIH HHS/ -- U01 NS058039/NS/NINDS NIH HHS/ -- U01 NS058039-03/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 10;475(7356):353-8. doi: 10.1038/nature10238.〈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/21743477" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arcobacter/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Calcium/metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; *Ion Channel Gating ; Ion Transport ; Models, Molecular ; Potassium/metabolism ; Potassium Channels/chemistry/metabolism ; Protein Conformation ; Sodium/metabolism ; Sodium Channel Blockers/chemistry/metabolism/pharmacology ; Sodium Channels/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity
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  • 60
    Publication Date: 2011-11-15
    Description: There is an emerging consensus that gene regulation evolves through changes in cis-regulatory elements and transcription factors. Although it is clear how nucleotide substitutions in cis-regulatory elements affect gene expression, it is not clear how amino-acid substitutions in transcription factors influence gene regulation. Here we show that amino-acid changes in the transcription factor CCAAT/enhancer binding protein-beta (CEBPB, also known as C/EBP-beta) in the stem-lineage of placental mammals changed the way it responds to cyclic AMP/protein kinase A (cAMP/PKA) signalling. By functionally analysing resurrected ancestral proteins, we identify three amino-acid substitutions in an internal regulatory domain of CEBPB that are responsible for the novel function. These amino-acid substitutions reorganize the location of key phosphorylation sites, introducing a new site and removing two ancestral sites, reversing the response of CEBPB to GSK-3beta-mediated phosphorylation from repression to activation. We conclude that changing the response of transcription factors to signalling pathways can be an important mechanism of gene regulatory evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lynch, Vincent J -- May, Gemma -- Wagner, Gunter P -- England -- Nature. 2011 Nov 13;480(7377):383-6. doi: 10.1038/nature10595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut 06511, USA. vincent.j.lynch@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080951" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Animals ; CCAAT-Enhancer-Binding Protein-beta/*chemistry/genetics/*metabolism ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *Evolution, Molecular ; Female ; Forkhead Transcription Factors/metabolism ; *Gene Expression Regulation ; Glycogen Synthase Kinase 3/metabolism ; HeLa Cells ; Humans ; Mammals ; Models, Molecular ; Phosphorylation/genetics ; Placenta ; Pregnancy ; Protein Conformation ; Protein Structure, Tertiary ; Structure-Activity Relationship
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  • 61
    Publication Date: 2011-07-01
    Description: Heavy-metal homeostasis and detoxification is crucial for cell viability. P-type ATPases of the class IB (PIB) are essential in these processes, actively extruding heavy metals from the cytoplasm of cells. Here we present the structure of a PIB-ATPase, a Legionella pneumophila CopA Cu(+)-ATPase, in a copper-free form, as determined by X-ray crystallography at 3.2 A resolution. The structure indicates a three-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to Ca(2+)-ATPase suggest an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. The structure also provides a framework to analyse missense mutations in the human ATP7A and ATP7B proteins associated with Menkes' and Wilson's diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gourdon, Pontus -- Liu, Xiang-Yu -- Skjorringe, Tina -- Morth, J Preben -- Moller, Lisbeth Birk -- Pedersen, Bjorn Panyella -- Nissen, Poul -- England -- Nature. 2011 Jun 29;475(7354):59-64. doi: 10.1038/nature10191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21716286" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/genetics ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Biological Transport ; Calcium ; Cation Transport Proteins/genetics ; Cell Membrane/metabolism ; Copper/*metabolism ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Hepatolenticular Degeneration/genetics ; Humans ; Legionella pneumophila/*chemistry ; Menkes Kinky Hair Syndrome/genetics ; Models, Molecular ; Mutation, Missense/genetics ; Protein Structure, Tertiary ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry ; Structure-Activity Relationship
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  • 62
    Publication Date: 2011-01-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mallet, James -- Dasmahapatra, Kanchon -- England -- Nature. 2011 Jan 6;469(7328):41-2. doi: 10.1038/469041a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21209654" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butterflies/physiology ; Catfishes/*anatomy & histology/classification/*physiology ; Competitive Behavior/*physiology ; *Ecosystem ; Food Chain ; *Models, Biological ; Molecular Mimicry/*physiology ; Phylogeny ; Pigmentation/physiology ; Predatory Behavior/physiology ; South America
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  • 63
    Publication Date: 2011-08-05
    Description: Vampire bats (Desmodus rotundus) are obligate blood feeders that have evolved specialized systems to suit their sanguinary lifestyle. Chief among such adaptations is the ability to detect infrared radiation as a means of locating hotspots on warm-blooded prey. Among vertebrates, only vampire bats, boas, pythons and pit vipers are capable of detecting infrared radiation. In each case, infrared signals are detected by trigeminal nerve fibres that innervate specialized pit organs on the animal's face. Thus, vampire bats and snakes have taken thermosensation to the extreme by developing specialized systems for detecting infrared radiation. As such, these creatures provide a window into the molecular and genetic mechanisms underlying evolutionary tuning of thermoreceptors in a species-specific or cell-type-specific manner. Previously, we have shown that snakes co-opt a non-heat-sensitive channel, vertebrate TRPA1 (transient receptor potential cation channel A1), to produce an infrared detector. Here we show that vampire bats tune a channel that is already heat-sensitive, TRPV1, by lowering its thermal activation threshold to about 30 degrees C. This is achieved through alternative splicing of TRPV1 transcripts to produce a channel with a truncated carboxy-terminal cytoplasmic domain. These splicing events occur exclusively in trigeminal ganglia, and not in dorsal root ganglia, thereby maintaining a role for TRPV1 as a detector of noxious heat in somatic afferents. This reflects a unique organization of the bat Trpv1 gene that we show to be characteristic of Laurasiatheria mammals (cows, dogs and moles), supporting a close phylogenetic relationship with bats. These findings reveal a novel molecular mechanism for physiological tuning of thermosensory nerve fibres.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535012/" 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/PMC3535012/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gracheva, Elena O -- Cordero-Morales, Julio F -- Gonzalez-Carcacia, Jose A -- Ingolia, Nicholas T -- Manno, Carlo -- Aranguren, Carla I -- Weissman, Jonathan S -- Julius, David -- GM080853/GM/NIGMS NIH HHS/ -- NS047723/NS/NINDS NIH HHS/ -- NS055299/NS/NINDS NIH HHS/ -- P01 AG010770/AG/NIA NIH HHS/ -- R01 NS055299/NS/NINDS NIH HHS/ -- R37 NS047723/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Aug 3;476(7358):88-91. doi: 10.1038/nature10245.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21814281" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Amino Acid Sequence ; Animals ; Cattle ; Chiroptera/anatomy & histology/classification/*genetics/*physiology ; Face/anatomy & histology/innervation ; Feeding Behavior/physiology ; HEK293 Cells ; Hot Temperature ; Humans ; *Infrared Rays ; Molecular Sequence Data ; Organ Specificity/genetics ; Phylogeny ; Predatory Behavior/physiology ; Protein Isoforms/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Sensation/*physiology ; TRPV Cation Channels/chemistry/*genetics/metabolism ; Trigeminal Ganglion/*metabolism
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  • 64
    Publication Date: 2011-07-08
    Description: The ribosome translates the genetic information encoded in messenger RNA into protein. Folded structures in the coding region of an mRNA represent a kinetic barrier that lowers the peptide elongation rate, as the ribosome must disrupt structures it encounters in the mRNA at its entry site to allow translocation to the next codon. Such structures are exploited by the cell to create diverse strategies for translation regulation, such as programmed frameshifting, the modulation of protein expression levels, ribosome localization and co-translational protein folding. Although strand separation activity is inherent to the ribosome, requiring no exogenous helicases, its mechanism is still unknown. Here, using a single-molecule optical tweezers assay on mRNA hairpins, we find that the translation rate of identical codons at the decoding centre is greatly influenced by the GC content of folded structures at the mRNA entry site. Furthermore, force applied to the ends of the hairpin to favour its unfolding significantly speeds translation. Quantitative analysis of the force dependence of its helicase activity reveals that the ribosome, unlike previously studied helicases, uses two distinct active mechanisms to unwind mRNA structure: it destabilizes the helical junction at the mRNA entry site by biasing its thermal fluctuations towards the open state, increasing the probability of the ribosome translocating unhindered; and it mechanically pulls apart the mRNA single strands of the closed junction during the conformational changes that accompany ribosome translocation. The second of these mechanisms ensures a minimal basal rate of translation in the cell; specialized, mechanically stable structures are required to stall the ribosome temporarily. Our results establish a quantitative mechanical basis for understanding the mechanism of regulation of the elongation rate of translation by structured mRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170678/" 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/PMC4170678/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qu, Xiaohui -- Wen, Jin-Der -- Lancaster, Laura -- Noller, Harry F -- Bustamante, Carlos -- Tinoco, Ignacio Jr -- R01 GM010840/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 6;475(7354):118-21. doi: 10.1038/nature10126.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jason L. Choy Laboratory of Single Molecule Biophysics and QB3 Institute, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734708" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Base Sequence ; Codon/genetics ; GC Rich Sequence/genetics ; HIV Reverse Transcriptase/metabolism ; Models, Molecular ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Optical Tweezers ; Peptide Chain Elongation, Translational ; *Protein Biosynthesis ; RNA Helicases/chemistry/metabolism ; RNA, Messenger/*chemistry/*genetics/metabolism ; Ribosomes/chemistry/enzymology/*metabolism ; Thermodynamics
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  • 65
    Publication Date: 2011-09-06
    Description: Post-translational modification of proteins by poly(ADP-ribosyl)ation regulates many cellular pathways that are critical for genome stability, including DNA repair, chromatin structure, mitosis and apoptosis. Poly(ADP-ribose) (PAR) is composed of repeating ADP-ribose units linked via a unique glycosidic ribose-ribose bond, and is synthesized from NAD by PAR polymerases. PAR glycohydrolase (PARG) is the only protein capable of specific hydrolysis of the ribose-ribose bonds present in PAR chains; its deficiency leads to cell death. Here we show that filamentous fungi and a number of bacteria possess a divergent form of PARG that has all the main characteristics of the human PARG enzyme. We present the first PARG crystal structure (derived from the bacterium Thermomonospora curvata), which reveals that the PARG catalytic domain is a distant member of the ubiquitous ADP-ribose-binding macrodomain family. High-resolution structures of T. curvata PARG in complexes with ADP-ribose and the PARG inhibitor ADP-HPD, complemented by biochemical studies, allow us to propose a model for PAR binding and catalysis by PARG. The insights into the PARG structure and catalytic mechanism should greatly improve our understanding of how PARG activity controls reversible protein poly(ADP-ribosyl)ation and potentially of how the defects in this regulation are linked to human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184140/" 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/PMC3184140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Slade, Dea -- Dunstan, Mark S -- Barkauskaite, Eva -- Weston, Ria -- Lafite, Pierre -- Dixon, Neil -- Ahel, Marijan -- Leys, David -- Ahel, Ivan -- A6058/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Sep 4;477(7366):616-20. doi: 10.1038/nature10404.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892188" target="_blank"〉PubMed〈/a〉
    Keywords: Actinomycetales/*enzymology ; Adenosine Diphosphate/analogs & derivatives/pharmacology ; Adenosine Diphosphate Ribose/chemistry/metabolism ; Amino Acid Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Evolution, Molecular ; Glycoside Hydrolases/antagonists & inhibitors/*chemistry/genetics/*metabolism ; Humans ; Hydrolysis ; Models, Molecular ; Molecular Sequence Data ; Phylogeny ; Poly Adenosine Diphosphate Ribose/chemistry/metabolism ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Protein Conformation ; Proteins/metabolism ; Pyrrolidines/pharmacology
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  • 66
    Publication Date: 2011-10-21
    Description: Changes in gene expression are thought to underlie many of the phenotypic differences between species. However, large-scale analyses of gene expression evolution were until recently prevented by technological limitations. Here we report the sequencing of polyadenylated RNA from six organs across ten species that represent all major mammalian lineages (placentals, marsupials and monotremes) and birds (the evolutionary outgroup), with the goal of understanding the dynamics of mammalian transcriptome evolution. We show that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation. Although gene expression evolution in mammals was strongly shaped by purifying selection, we identify numerous potentially selectively driven expression switches, which occurred at different rates across lineages and tissues and which probably contributed to the specific organ biology of various mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brawand, David -- Soumillon, Magali -- Necsulea, Anamaria -- Julien, Philippe -- Csardi, Gabor -- Harrigan, Patrick -- Weier, Manuela -- Liechti, Angelica -- Aximu-Petri, Ayinuer -- Kircher, Martin -- Albert, Frank W -- Zeller, Ulrich -- Khaitovich, Philipp -- Grutzner, Frank -- Bergmann, Sven -- Nielsen, Rasmus -- Paabo, Svante -- Kaessmann, Henrik -- England -- Nature. 2011 Oct 19;478(7369):343-8. doi: 10.1038/nature10532.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22012392" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Evolution, Molecular ; *Gene Expression Profiling ; Humans ; Phylogeny ; Principal Component Analysis ; RNA, Messenger/*genetics ; X Chromosome/genetics
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  • 67
    Publication Date: 2011-10-21
    Description: Extremophilic organisms require specialized enzymes for their exotic metabolisms. Acid-loving thermophilic Archaea that live in the mudpots of volcanic solfataras obtain their energy from reduced sulphur compounds such as hydrogen sulphide (H(2)S) and carbon disulphide (CS(2)). The oxidation of these compounds into sulphuric acid creates the extremely acidic environment that characterizes solfataras. The hyperthermophilic Acidianus strain A1-3, which was isolated from the fumarolic, ancient sauna building at the Solfatara volcano (Naples, Italy), was shown to rapidly convert CS(2) into H(2)S and carbon dioxide (CO(2)), but nothing has been known about the modes of action and the evolution of the enzyme(s) involved. Here we describe the structure, the proposed mechanism and evolution of a CS(2) hydrolase from Acidianus A1-3. The enzyme monomer displays a typical beta-carbonic anhydrase fold and active site, yet CO(2) is not one of its substrates. Owing to large carboxy- and amino-terminal arms, an unusual hexadecameric catenane oligomer has evolved. This structure results in the blocking of the entrance to the active site that is found in canonical beta-carbonic anhydrases and the formation of a single 15-A-long, highly hydrophobic tunnel that functions as a specificity filter. The tunnel determines the enzyme's substrate specificity for CS(2), which is hydrophobic. The transposon sequences that surround the gene encoding this CS(2) hydrolase point to horizontal gene transfer as a mechanism for its acquisition during evolution. Our results show how the ancient beta-carbonic anhydrase, which is central to global carbon metabolism, was transformed by divergent evolution into a crucial enzyme in CS(2) metabolism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smeulders, Marjan J -- Barends, Thomas R M -- Pol, Arjan -- Scherer, Anna -- Zandvoort, Marcel H -- Udvarhelyi, Aniko -- Khadem, Ahmad F -- Menzel, Andreas -- Hermans, John -- Shoeman, Robert L -- Wessels, Hans J C T -- van den Heuvel, Lambert P -- Russ, Lina -- Schlichting, Ilme -- Jetten, Mike S M -- Op den Camp, Huub J M -- England -- Nature. 2011 Oct 19;478(7369):412-6. doi: 10.1038/nature10464.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22012399" target="_blank"〉PubMed〈/a〉
    Keywords: Acidianus/classification/*enzymology/genetics ; Carbon Disulfide/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; *Evolution, Molecular ; Hydrolases/chemistry/*genetics ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Phylogeny ; Protein Structure, Tertiary
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  • 68
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2011-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Weil, Anne -- England -- Nature. 2011 Apr 14;472(7342):174-6. doi: 10.1038/472174a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490663" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Cartilage/anatomy & histology ; China ; Ear Ossicles/*anatomy & histology/physiology ; *Fossils ; History, Ancient ; Jaw/*anatomy & histology ; Mammals/*anatomy & histology/*classification ; Phylogeny ; Reptiles/anatomy & histology ; Tympanic Membrane/anatomy & histology
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  • 69
    Publication Date: 2011-11-01
    Description: Horizontal gene transfer (HGT), the acquisition of genetic material from non-parental lineages, is known to be important in bacterial evolution. In particular, HGT provides rapid access to genetic innovations, allowing traits such as virulence, antibiotic resistance and xenobiotic metabolism to spread through the human microbiome. Recent anecdotal studies providing snapshots of active gene flow on the human body have highlighted the need to determine the frequency of such recent transfers and the forces that govern these events. Here we report the discovery and characterization of a vast, human-associated network of gene exchange, large enough to directly compare the principal forces shaping HGT. We show that this network of 10,770 unique, recently transferred (more than 99% nucleotide identity) genes found in 2,235 full bacterial genomes, is shaped principally by ecology rather than geography or phylogeny, with most gene exchange occurring between isolates from ecologically similar, but geographically separated, environments. For example, we observe 25-fold more HGT between human-associated bacteria than among ecologically diverse non-human isolates (P = 3.0 x 10(-270)). We show that within the human microbiome this ecological architecture continues across multiple spatial scales, functional classes and ecological niches with transfer further enriched among bacteria that inhabit the same body site, have the same oxygen tolerance or have the same ability to cause disease. This structure offers a window into the molecular traits that define ecological niches, insight that we use to uncover sources of antibiotic resistance and identify genes associated with the pathology of meningitis and other diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smillie, Chris S -- Smith, Mark B -- Friedman, Jonathan -- Cordero, Otto X -- David, Lawrence A -- Alm, Eric J -- England -- Nature. 2011 Oct 30;480(7376):241-4. doi: 10.1038/nature10571.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Computational and Systems Biology Initiative, 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/22037308" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*genetics/isolation & purification/metabolism/pathogenicity ; *Biological Evolution ; Drug Resistance, Microbial/genetics ; *Ecosystem ; Gene Transfer, Horizontal/*genetics ; Genes, Bacterial/genetics ; Genome, Bacterial/genetics ; Humans ; Metagenome/*genetics ; Organ Specificity ; Phylogeny ; Phylogeography ; RNA, Ribosomal, 16S/genetics
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  • 70
    Publication Date: 2011-06-24
    Description: The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191(5.39) and/or Lys 179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131495/" 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/PMC3131495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimamura, Tatsuro -- Shiroishi, Mitsunori -- Weyand, Simone -- Tsujimoto, Hirokazu -- Winter, Graeme -- Katritch, Vsevolod -- Abagyan, Ruben -- Cherezov, Vadim -- Liu, Wei -- Han, Gye Won -- Kobayashi, Takuya -- Stevens, Raymond C -- Iwata, So -- 062164/ Z/00/Z/Wellcome Trust/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-07/GM/NIGMS NIH HHS/ -- R01 GM071872/GM/NIGMS NIH HHS/ -- R01 GM071872-02/GM/NIGMS NIH HHS/ -- R01 GM071872-08/GM/NIGMS NIH HHS/ -- R01 GM089857/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jun 22;475(7354):65-70. doi: 10.1038/nature10236.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21697825" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Doxepin/chemistry/*metabolism ; Histamine Antagonists/chemistry/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Isomerism ; Ligands ; Models, Molecular ; Phosphates/chemistry/metabolism ; Protein Binding ; Protein Conformation ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Dopamine D3/chemistry ; Receptors, Histamine H1/*chemistry/*metabolism ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 71
    Publication Date: 2011-01-14
    Description: G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human beta(2) adrenergic receptor (beta(2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive beta(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 A outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058308/" 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/PMC3058308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasmussen, Soren G F -- Choi, Hee-Jung -- Fung, Juan Jose -- Pardon, Els -- Casarosa, Paola -- Chae, Pil Seok -- Devree, Brian T -- Rosenbaum, Daniel M -- Thian, Foon Sun -- Kobilka, Tong Sun -- Schnapp, Andreas -- Konetzki, Ingo -- Sunahara, Roger K -- Gellman, Samuel H -- Pautsch, Alexander -- Steyaert, Jan -- Weis, William I -- Kobilka, Brian K -- GM083118/GM/NIGMS NIH HHS/ -- GM56169/GM/NIGMS NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P01 GM75913/GM/NIGMS NIH HHS/ -- P60DK-20572/DK/NIDDK NIH HHS/ -- R01 GM068603/GM/NIGMS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 GM083118-04/GM/NIGMS NIH HHS/ -- R37 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471-21/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Jan 13;469(7329):175-80. doi: 10.1038/nature09648.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21228869" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor ; Agonists/*chemistry/immunology/metabolism/*pharmacology ; Animals ; Binding Sites ; Camelids, New World ; Crystallography, X-Ray ; Drug Inverse Agonism ; Humans ; Immunoglobulin Fragments/*chemistry/*immunology/metabolism/pharmacology ; Ligands ; Models, Molecular ; Movement/drug effects ; Nanostructures/*chemistry ; Opsins/agonists/chemistry/metabolism ; Propanolamines/chemistry/metabolism/pharmacology ; Protein Conformation/drug effects ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism ; Viral Proteins/chemistry/metabolism
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  • 72
    Publication Date: 2011-01-14
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804163/" 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/PMC3804163/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sprang, Stephen R -- R56 DK046371/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jan 13;469(7329):172-3. doi: 10.1038/469172a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21228868" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic Agonists/chemistry/metabolism/*pharmacology ; Adrenergic Antagonists/chemistry/metabolism/*pharmacology ; Animals ; Crystallography, X-Ray ; Drug Partial Agonism ; Heterotrimeric GTP-Binding Proteins/*metabolism ; Humans ; Models, Molecular ; Protein Conformation/drug effects ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-1/*chemistry/*metabolism ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism ; Viral Proteins/chemistry/metabolism
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  • 73
    Publication Date: 2011-09-23
    Description: Bacteria and archaea acquire resistance to viruses and plasmids by integrating short fragments of foreign DNA into clustered regularly interspaced short palindromic repeats (CRISPRs). These repetitive loci maintain a genetic record of all prior encounters with foreign transgressors. CRISPRs are transcribed and the long primary transcript is processed into a library of short CRISPR-derived RNAs (crRNAs) that contain a unique sequence complementary to a foreign nucleic-acid challenger. In Escherichia coli, crRNAs are incorporated into a multisubunit surveillance complex called Cascade (CRISPR-associated complex for antiviral defence), which is required for protection against bacteriophages. Here we use cryo-electron microscopy to determine the subnanometre structures of Cascade before and after binding to a target sequence. These structures reveal a sea-horse-shaped architecture in which the crRNA is displayed along a helical arrangement of protein subunits that protect the crRNA from degradation while maintaining its availability for base pairing. Cascade engages invading nucleic acids through high-affinity base-pairing interactions near the 5' end of the crRNA. Base pairing extends along the crRNA, resulting in a series of short helical segments that trigger a concerted conformational change. This conformational rearrangement may serve as a signal that recruits a trans-acting nuclease (Cas3) for destruction of invading nucleic-acid sequences.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165517/" 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/PMC4165517/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wiedenheft, Blake -- Lander, Gabriel C -- Zhou, Kaihong -- Jore, Matthijs M -- Brouns, Stan J J -- van der Oost, John -- Doudna, Jennifer A -- Nogales, Eva -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 21;477(7365):486-9. doi: 10.1038/nature10402.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21938068" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Cryoelectron Microscopy ; Escherichia coli K12/chemistry/*genetics/*immunology/virology ; Escherichia coli Proteins/chemistry/immunology/*ultrastructure ; Inverted Repeat Sequences/genetics/immunology ; Macromolecular Substances/*chemistry/metabolism/*ultrastructure ; Models, Biological ; Models, Molecular ; Protein Conformation ; RNA, Bacterial/genetics/*immunology/*ultrastructure
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  • 74
    Publication Date: 2011-10-11
    Description: Fructose-1,6-bisphosphate (FBP) aldolase/phosphatase is a bifunctional, thermostable enzyme that catalyses two subsequent steps in gluconeogenesis in most archaea and in deeply branching bacterial lineages. It mediates the aldol condensation of heat-labile dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP) to FBP, as well as the subsequent, irreversible hydrolysis of the product to yield the stable fructose-6-phosphate (F6P) and inorganic phosphate; no reaction intermediates are released. Here we present a series of structural snapshots of the reaction that reveal a substantial remodelling of the active site through the movement of loop regions that create different catalytic functionalities at the same location. We have solved the three-dimensional structures of FBP aldolase/phosphatase from thermophilic Thermoproteus neutrophilus in a ligand-free state as well as in complex with the substrates DHAP and FBP and the product F6P to resolutions up to 1.3 A. In conjunction with mutagenesis data, this pinpoints the residues required for the two reaction steps and shows that the sequential binding of additional Mg(2+) cations reversibly facilitates the reaction. FBP aldolase/phosphatase is an ancestral gluconeogenic enzyme optimized for high ambient temperatures, and our work resolves how consecutive structural rearrangements reorganize the catalytic centre of the protein to carry out two canonical reactions in a very non-canonical type of bifunctionality.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Du, Juan -- Say, Rafael F -- Lu, Wei -- Fuchs, Georg -- Einsle, Oliver -- England -- Nature. 2011 Oct 9;478(7370):534-7. doi: 10.1038/nature10458.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lehrstuhl fur Biochemie, Institut fur organische Chemie und Biochemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21983965" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Dihydroxyacetone Phosphate/metabolism ; Fructose-Bisphosphate Aldolase/*chemistry/*metabolism ; Fructosediphosphates/metabolism ; Fructosephosphates/metabolism ; Glyceraldehyde 3-Phosphate/metabolism ; Magnesium/metabolism ; Models, Molecular ; Phosphoric Monoester Hydrolases/*chemistry/*metabolism ; Protein Conformation ; Schiff Bases/chemistry ; Temperature ; Thermoproteus/*enzymology
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  • 75
    Publication Date: 2011-08-30
    Description: The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signalling in cells. In particular, phosphatidylinositol 4,5-bisphosphate (PIP(2)), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels. PIP(2) is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell's resting membrane potential. However, the molecular mechanism by which PIP(2) exerts its action is unknown. Here we present the X-ray crystal structure of a Kir2.2 channel in complex with a short-chain (dioctanoyl) derivative of PIP(2). We found that PIP(2) binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain (CTD). The PIP(2)-binding site consists of a conserved non-specific phospholipid-binding region in the TMD and a specific phosphatidylinositol-binding region in the CTD. On PIP(2) binding, a flexible expansion linker contracts to a compact helical structure, the CTD translates 6 A and becomes tethered to the TMD and the inner helix gate begins to open. In contrast, the small anionic lipid dioctanoyl glycerol pyrophosphatidic acid (PPA) also binds to the non-specific TMD region, but not to the specific phosphatidylinositol region, and thus fails to engage the CTD or open the channel. Our results show how PIP(2) can control the resting membrane potential through a specific ion-channel-receptor-ligand interaction that brings about a large conformational change, analogous to neurotransmitter activation of ion channels at synapses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324908/" 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/PMC3324908/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hansen, Scott B -- Tao, Xiao -- MacKinnon, Roderick -- P30 EB009998/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Aug 28;477(7365):495-8. doi: 10.1038/nature10370.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology & Biophysics, The Rockefeller University, Howard Hughes Medical Institute, 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/21874019" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Cell Membrane/metabolism ; Chickens/genetics ; Conserved Sequence ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Ion Channel Gating/drug effects ; Membrane Potentials/drug effects ; Models, Molecular ; Molecular Sequence Data ; Patch-Clamp Techniques ; Phosphatidic Acids/metabolism/pharmacology ; Phosphatidylinositol 4,5-Diphosphate/chemistry/*metabolism/pharmacology ; Potassium Channels, Inwardly Rectifying/*chemistry/genetics/*metabolism ; Protein Structure, Tertiary/drug effects ; Protein Subunits/chemistry/metabolism ; Substrate Specificity
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  • 76
    Publication Date: 2011-11-25
    Description: Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded beta-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406929/" 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/PMC3406929/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Pancera, Marie -- Carrico, Chris -- Gorman, Jason -- Julien, Jean-Philippe -- Khayat, Reza -- Louder, Robert -- Pejchal, Robert -- Sastry, Mallika -- Dai, Kaifan -- O'Dell, Sijy -- Patel, Nikita -- Shahzad-ul-Hussan, Syed -- Yang, Yongping -- Zhang, Baoshan -- Zhou, Tongqing -- Zhu, Jiang -- Boyington, Jeffrey C -- Chuang, Gwo-Yu -- Diwanji, Devan -- Georgiev, Ivelin -- Kwon, Young Do -- Lee, Doyung -- Louder, Mark K -- Moquin, Stephanie -- Schmidt, Stephen D -- Yang, Zhi-Yong -- Bonsignori, Mattia -- Crump, John A -- Kapiga, Saidi H -- Sam, Noel E -- Haynes, Barton F -- Burton, Dennis R -- Koff, Wayne C -- Walker, Laura M -- Phogat, Sanjay -- Wyatt, Richard -- Orwenyo, Jared -- Wang, Lai-Xi -- Arthos, James -- Bewley, Carole A -- Mascola, John R -- Nabel, Gary J -- Schief, William R -- Ward, Andrew B -- Wilson, Ian A -- Kwong, Peter D -- R01 AI033292/AI/NIAID NIH HHS/ -- R01 AI084817/AI/NIAID NIH HHS/ -- RR017573/RR/NCRR NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 23;480(7377):336-43. doi: 10.1038/nature10696.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22113616" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Motifs ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/*immunology ; Antibody Affinity/immunology ; Antibody Specificity/*immunology ; Antigen-Antibody Complex/chemistry/immunology ; Binding Sites, Antibody/immunology ; Conserved Sequence ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; Glycopeptides/chemistry/immunology ; Glycosylation ; HIV Antibodies/chemistry/*immunology ; HIV Envelope Protein gp120/*chemistry/*immunology ; HIV-1/*chemistry/*immunology ; Hydrogen Bonding ; Immune Evasion ; Models, Molecular ; Molecular Sequence Data ; Polysaccharides/chemistry/immunology ; Protein Structure, Quaternary ; Protein Structure, Tertiary
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  • 77
    Publication Date: 2011-04-19
    Description: T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gammat (RORalpha and RORgammat, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORalpha and RORgammat and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORalpha and RORgammat, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORalpha and RORgammat to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" 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/PMC3148894/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Kumar, Naresh -- Nuhant, Philippe -- Wang, Yongjun -- Lauer, Janelle L -- Liu, Jin -- Istrate, Monica A -- Kamenecka, Theodore M -- Roush, William R -- Vidovic, Dusica -- Schurer, Stephan C -- Xu, Jihong -- Wagoner, Gail -- Drew, Paul D -- Griffin, Patrick R -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- GM084041/GM/NIGMS NIH HHS/ -- MH084512/MH/NIMH NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-06/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- U54 MH084512-02/MH/NIMH NIH HHS/ -- U54MH074404/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):491-4. doi: 10.1038/nature10075. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/*drug effects/immunology ; Cell Differentiation/*drug effects ; Drug Inverse Agonism ; HEK293 Cells ; Humans ; Interleukin-17/biosynthesis/immunology ; Interleukins/biosynthesis/immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Nuclear Receptor Subfamily 1, Group F, Member 1/antagonists & ; inhibitors/genetics/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & ; inhibitors/genetics/metabolism ; Sulfonamides/*pharmacology ; Th17 Cells/*cytology/drug effects/*immunology/secretion ; Thiazoles/*pharmacology
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  • 78
    Publication Date: 2011-10-04
    Description: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" 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/PMC3679520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Prinjha, Rab K -- Dittmann, Antje -- Giotopoulos, George -- Bantscheff, Marcus -- Chan, Wai-In -- Robson, Samuel C -- Chung, Chun-wa -- Hopf, Carsten -- Savitski, Mikhail M -- Huthmacher, Carola -- Gudgin, Emma -- Lugo, Dave -- Beinke, Soren -- Chapman, Trevor D -- Roberts, Emma J -- Soden, Peter E -- Auger, Kurt R -- Mirguet, Olivier -- Doehner, Konstanze -- Delwel, Ruud -- Burnett, Alan K -- Jeffrey, Phillip -- Drewes, Gerard -- Lee, Kevin -- Huntly, Brian J P -- Kouzarides, Tony -- 092096/Wellcome Trust/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- G116/187/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Oct 2;478(7370):529-33. doi: 10.1038/nature10509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964340" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromatin Immunoprecipitation ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds with 4 or More Rings/pharmacology/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Myeloid-Lymphoid Leukemia Protein/*metabolism ; Oncogene Proteins, Fusion/*metabolism ; Protein Binding/drug effects ; Proteomics ; Transcription Factors/*antagonists & inhibitors/*metabolism ; Transcription, Genetic/drug effects
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  • 79
    Publication Date: 2011-03-29
    Description: Superfamily 1 and superfamily 2 RNA helicases are ubiquitous messenger-RNA-protein complex (mRNP) remodelling enzymes that have critical roles in all aspects of RNA metabolism. The superfamily 2 DEAD-box ATPase Dbp5 (human DDX19) functions in mRNA export and is thought to remodel mRNPs at the nuclear pore complex (NPC). Dbp5 is localized to the NPC via an interaction with Nup159 (NUP214 in vertebrates) and is locally activated there by Gle1 together with the small-molecule inositol hexakisphosphate (InsP(6)). Local activation of Dbp5 at the NPC by Gle1 is essential for mRNA export in vivo; however, the mechanistic role of Dbp5 in mRNP export is poorly understood and it is not known how Gle1(InsP6) and Nup159 regulate the activity of Dbp5. Here we report, from yeast, structures of Dbp5 in complex with Gle1(InsP6), Nup159/Gle1(InsP6) and RNA. These structures reveal that InsP(6) functions as a small-molecule tether for the Gle1-Dbp5 interaction. Surprisingly, the Gle1(InsP6)-Dbp5 complex is structurally similar to another DEAD-box ATPase complex essential for translation initiation, eIF4G-eIF4A, and we demonstrate that Gle1(InsP6) and eIF4G both activate their DEAD-box partner by stimulating RNA release. Furthermore, Gle1(InsP6) relieves Dbp5 autoregulation and cooperates with Nup159 in stabilizing an open Dbp5 intermediate that precludes RNA binding. These findings explain how Gle1(InsP6), Nup159 and Dbp5 collaborate in mRNA export and provide a general mechanism for DEAD-box ATPase regulation by Gle1/eIF4G-like activators.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078754/" 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/PMC3078754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Montpetit, Ben -- Thomsen, Nathan D -- Helmke, Kara J -- Seeliger, Markus A -- Berger, James M -- Weis, Karsten -- R00 GM080097/GM/NIGMS NIH HHS/ -- R01 GM058065/GM/NIGMS NIH HHS/ -- R01 GM058065-13/GM/NIGMS NIH HHS/ -- R01GM58065/GM/NIGMS NIH HHS/ -- RC1 GM091533/GM/NIGMS NIH HHS/ -- RC1 GM091533-02/GM/NIGMS NIH HHS/ -- RC1GM91533/GM/NIGMS NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Apr 14;472(7342):238-42. doi: 10.1038/nature09862. Epub 2011 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cell and Developmental Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21441902" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/*metabolism ; DEAD-box RNA Helicases/chemistry/*metabolism ; Enzyme Activation ; Eukaryotic Initiation Factor-4A/chemistry/metabolism ; Eukaryotic Initiation Factor-4G/chemistry/metabolism ; Models, Biological ; Models, Molecular ; Nuclear Pore Complex Proteins/chemistry/genetics/*metabolism ; Nucleocytoplasmic Transport Proteins/metabolism ; Phytic Acid/*metabolism ; Protein Conformation ; *RNA Transport ; RNA, Fungal/metabolism ; RNA, Messenger/*metabolism ; Saccharomyces cerevisiae/cytology/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism
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  • 80
    Publication Date: 2011-10-14
    Description: Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690193/" 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/PMC3690193/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bos, Kirsten I -- Schuenemann, Verena J -- Golding, G Brian -- Burbano, Hernan A -- Waglechner, Nicholas -- Coombes, Brian K -- McPhee, Joseph B -- DeWitte, Sharon N -- Meyer, Matthias -- Schmedes, Sarah -- Wood, James -- Earn, David J D -- Herring, D Ann -- Bauer, Peter -- Poinar, Hendrik N -- Krause, Johannes -- R24 HD044943/HD/NICHD NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Oct 12;478(7370):506-10. doi: 10.1038/nature10549.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McMaster Ancient DNA Centre, Department of Anthropology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993626" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosomes, Bacterial/genetics ; Contig Mapping ; Dental Pulp/microbiology ; Evolution, Molecular ; Genome, Bacterial/*genetics ; History, Medieval ; Humans ; London/epidemiology ; Molecular Sequence Data ; Phylogeny ; Plague/epidemiology/*microbiology/transmission ; Plasmids/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Virulence/genetics ; Yersinia pestis/classification/*genetics/*isolation & purification
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  • 81
    Publication Date: 2011-04-15
    Description: The transference of post-dentary jaw elements to the cranium of mammals as auditory ossicles is one of the central topics in evolutionary biology of vertebrates. Homologies of these bones among jawed vertebrates have long been demonstrated by developmental studies; but fossils illuminating this critical transference are sparse and often ambiguous. Here we report the first unambiguous ectotympanic (angular), malleus (articular and prearticular) and incus (quadrate) of an Early Cretaceous eutriconodont mammal from the Jehol Biota, Liaoning, China. The ectotympanic and malleus have lost their direct contact with the dentary bone but still connect the ossified Meckel's cartilage (OMC); we hypothesize that the OMC serves as a stabilizing mechanism bridging the dentary and the detached ossicles during mammalian evolution. This transitional mammalian middle ear narrows the morphological gap between the mandibular middle ear in basal mammaliaforms and the definitive mammalian middle ear (DMME) of extant mammals; it reveals complex changes contributing to the detachment of ear ossicles during mammalian evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meng, Jin -- Wang, Yuanqing -- Li, Chuankui -- England -- Nature. 2011 Apr 14;472(7342):181-5. doi: 10.1038/nature09921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Paleontology, American Museum of Natural History, Central Park West at 79th Street, New York, New York 10024, USA. jmeng@amnh.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490668" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Cartilage/anatomy & histology ; China ; Ear Ossicles/anatomy & histology/physiology ; Ear, Middle/*anatomy & histology/physiology ; Extinction, Biological ; *Fossils ; History, Ancient ; Jaw/anatomy & histology ; Mammals/*anatomy & histology/*classification ; Phylogeny ; Tympanic Membrane/anatomy & histology
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  • 82
    Publication Date: 2011-02-26
    Description: Gram-negative bacteria, such as Escherichia coli, expel toxic chemicals through tripartite efflux pumps that span both the inner and outer membrane. The three parts are an inner membrane, substrate-binding transporter; a membrane fusion protein; and an outer-membrane-anchored channel. The fusion protein connects the transporter to the channel within the periplasmic space. A crystallographic model of this tripartite efflux complex has been unavailable because co-crystallization of the various components of the system has proven to be extremely difficult. We previously described the crystal structures of both the inner membrane transporter CusA and the membrane fusion protein CusB of the CusCBA efflux system of E. coli. Here we report the co-crystal structure of the CusBA efflux complex, showing that the transporter (or pump) CusA, which is present as a trimer, interacts with six CusB protomers and that the periplasmic domain of CusA is involved in these interactions. The six CusB molecules seem to form a continuous channel. The affinity of the CusA and CusB interaction was found to be in the micromolar range. Finally, we have predicted a three-dimensional structure for the trimeric CusC outer membrane channel and developed a model of the tripartite efflux assemblage. This CusC(3)-CusB(6)-CusA(3) model shows a 750-kilodalton efflux complex that spans the entire bacterial cell envelope and exports Cu I and Ag I ions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078058/" 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/PMC3078058/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Chih-Chia -- Long, Feng -- Zimmermann, Michael T -- Rajashankar, Kanagalaghatta R -- Jernigan, Robert L -- Yu, Edward W -- R01 GM072014/GM/NIGMS NIH HHS/ -- R01 GM074027/GM/NIGMS NIH HHS/ -- R01 GM074027-05/GM/NIGMS NIH HHS/ -- R01 GM086431/GM/NIGMS NIH HHS/ -- R01 GM086431-01A2/GM/NIGMS NIH HHS/ -- R01GM072014/GM/NIGMS NIH HHS/ -- R01GM074027/GM/NIGMS NIH HHS/ -- R01GM081680/GM/NIGMS NIH HHS/ -- R01GM086431/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Feb 24;470(7335):558-62. doi: 10.1038/nature09743.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350490" target="_blank"〉PubMed〈/a〉
    Keywords: Copper/metabolism ; Crystallization ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/metabolism ; Membrane Transport Proteins/*chemistry/metabolism ; Metals, Heavy/*metabolism ; Models, Molecular ; Multiprotein Complexes/*chemistry/metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Silver/metabolism ; Static Electricity
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  • 83
    Publication Date: 2011-06-10
    Description: The air-water interface is perhaps the most common liquid interface. It covers more than 70 per cent of the Earth's surface and strongly affects atmospheric, aerosol and environmental chemistry. The air-water interface has also attracted much interest as a model system that allows rigorous tests of theory, with one fundamental question being just how thin it is. Theoretical studies have suggested a surprisingly short 'healing length' of about 3 angstroms (1 A = 0.1 nm), with the bulk-phase properties of water recovered within the top few monolayers. However, direct experimental evidence has been elusive owing to the difficulty of depth-profiling the liquid surface on the angstrom scale. Most physical, chemical and biological properties of water, such as viscosity, solvation, wetting and the hydrophobic effect, are determined by its hydrogen-bond network. This can be probed by observing the lineshape of the OH-stretch mode, the frequency shift of which is related to the hydrogen-bond strength. Here we report a combined experimental and theoretical study of the air-water interface using surface-selective heterodyne-detected vibrational sum frequency spectroscopy to focus on the 'free OD' transition found only in the topmost water layer. By using deuterated water and isotopic dilution to reveal the vibrational coupling mechanism, we find that the free OD stretch is affected only by intramolecular coupling to the stretching of the other OD group on the same molecule. The other OD stretch frequency indicates the strength of one of the first hydrogen bonds encountered at the surface; this is the donor hydrogen bond of the water molecule straddling the interface, which we find to be only slightly weaker than bulk-phase water hydrogen bonds. We infer from this observation a remarkably fast onset of bulk-phase behaviour on crossing from the air into the water phase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stiopkin, Igor V -- Weeraman, Champika -- Pieniazek, Piotr A -- Shalhout, Fadel Y -- Skinner, James L -- Benderskii, Alexander V -- England -- Nature. 2011 Jun 8;474(7350):192-5. doi: 10.1038/nature10173.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654801" target="_blank"〉PubMed〈/a〉
    Keywords: Air/*analysis ; Atmosphere/chemistry ; Deuterium/chemistry ; Hydrogen Bonding ; Models, Chemical ; Models, Molecular ; Oxygen/chemistry ; Vibration ; Water/analysis/*chemistry
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  • 84
    Publication Date: 2011-08-09
    Description: Complex I is the first and largest enzyme of the respiratory chain, coupling electron transfer between NADH and ubiquinone to the translocation of four protons across the membrane. It has a central role in cellular energy production and has been implicated in many human neurodegenerative diseases. The L-shaped enzyme consists of hydrophilic and membrane domains. Previously, we determined the structure of the hydrophilic domain. Here we report the crystal structure of the Esherichia coli complex I membrane domain at 3.0 A resolution. It includes six subunits, NuoL, NuoM, NuoN, NuoA, NuoJ and NuoK, with 55 transmembrane helices. The fold of the homologous antiporter-like subunits L, M and N is novel, with two inverted structural repeats of five transmembrane helices arranged, unusually, face-to-back. Each repeat includes a discontinuous transmembrane helix and forms half of a channel across the membrane. A network of conserved polar residues connects the two half-channels, completing the proton translocation pathway. Unexpectedly, lysines rather than carboxylate residues act as the main elements of the proton pump in these subunits. The fourth probable proton-translocation channel is at the interface of subunits N, K, J and A. The structure indicates that proton translocation in complex I, uniquely, involves coordinated conformational changes in six symmetrical structural elements.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Efremov, Rouslan G -- Sazanov, Leonid A -- MC_U105674180/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Aug 7;476(7361):414-20. doi: 10.1038/nature10330.〈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/21822288" target="_blank"〉PubMed〈/a〉
    Keywords: Antiporters/chemistry/metabolism ; Cell Membrane/*metabolism ; Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/*metabolism ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Ion Transport ; Lysine/metabolism ; Models, Molecular ; NAD/metabolism ; NADH Dehydrogenase/chemistry/metabolism ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protons ; Ubiquinone/metabolism
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  • 85
    Publication Date: 2011-07-12
    Description: In eukaryotes, accurate chromosome segregation during mitosis and meiosis is coordinated by kinetochores, which are unique chromosomal sites for microtubule attachment. Centromeres specify the kinetochore formation sites on individual chromosomes, and are epigenetically marked by the assembly of nucleosomes containing the centromere-specific histone H3 variant, CENP-A. Although the underlying mechanism is unclear, centromere inheritance is probably dictated by the architecture of the centromeric nucleosome. Here we report the crystal structure of the human centromeric nucleosome containing CENP-A and its cognate alpha-satellite DNA derivative (147 base pairs). In the human CENP-A nucleosome, the DNA is wrapped around the histone octamer, consisting of two each of histones H2A, H2B, H4 and CENP-A, in a left-handed orientation. However, unlike the canonical H3 nucleosome, only the central 121 base pairs of the DNA are visible. The thirteen base pairs from both ends of the DNA are invisible in the crystal structure, and the alphaN helix of CENP-A is shorter than that of H3, which is known to be important for the orientation of the DNA ends in the canonical H3 nucleosome. A structural comparison of the CENP-A and H3 nucleosomes revealed that CENP-A contains two extra amino acid residues (Arg 80 and Gly 81) in the loop 1 region, which is completely exposed to the solvent. Mutations of the CENP-A loop 1 residues reduced CENP-A retention at the centromeres in human cells. Therefore, the CENP-A loop 1 may function in stabilizing the centromeric chromatin containing CENP-A, possibly by providing a binding site for trans-acting factors. The structure provides the first atomic-resolution picture of the centromere-specific nucleosome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tachiwana, Hiroaki -- Kagawa, Wataru -- Shiga, Tatsuya -- Osakabe, Akihisa -- Miya, Yuta -- Saito, Kengo -- Hayashi-Takanaka, Yoko -- Oda, Takashi -- Sato, Mamoru -- Park, Sam-Yong -- Kimura, Hiroshi -- Kurumizaka, Hitoshi -- England -- Nature. 2011 Jul 10;476(7359):232-5. doi: 10.1038/nature10258.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21743476" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Autoantigens/*chemistry/metabolism ; Base Sequence ; Chromosomal Proteins, Non-Histone/*chemistry/metabolism ; Crystallography, X-Ray ; DNA/*chemistry/genetics/metabolism ; Histones/*chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Conformation ; Molecular Sequence Data ; Nucleosomes/*chemistry/genetics/metabolism
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  • 86
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    Nature Publishing Group (NPG)
    Publication Date: 2011-10-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2011 Oct 25;478(7370):444-6. doi: 10.1038/478444a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22031418" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; DNA Contamination ; Disease Outbreaks ; Evolution, Molecular ; Genome, Bacterial/*genetics ; History, 19th Century ; History, Ancient ; History, Medieval ; Humans ; Insect Vectors/microbiology ; London/epidemiology ; Phylogeny ; Plague/epidemiology/history/*microbiology/transmission ; Polymerase Chain Reaction ; Rats ; Reproducibility of Results ; Yersinia pestis/classification/*genetics/isolation & purification
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  • 87
    Publication Date: 2011-10-18
    Description: Light is a fundamental signal that regulates important physiological processes such as development and circadian rhythm in living organisms. Phytochromes form a major family of photoreceptors responsible for red light perception in plants, fungi and bacteria. They undergo reversible photoconversion between red-absorbing (Pr) and far-red-absorbing (Pfr) states, thereby ultimately converting a light signal into a distinct biological signal that mediates subsequent cellular responses. Several structures of microbial phytochromes have been determined in their dark-adapted Pr or Pfr states. However, the structural nature of initial photochemical events has not been characterized by crystallography. Here we report the crystal structures of three intermediates in the photoreaction of Pseudomonas aeruginosa bacteriophytochrome (PaBphP). We used cryotrapping crystallography to capture intermediates, and followed structural changes by scanning the temperature at which the photoreaction proceeded. Light-induced conformational changes in PaBphP originate in ring D of the biliverdin (BV) chromophore, and E-to-Z isomerization about the C(15) = C(16) double bond between rings C and D is the initial photochemical event. As the chromophore relaxes, the twist of the C(15) methine bridge about its two dihedral angles is reversed. Structural changes extend further to rings B and A, and to the surrounding protein regions. These data indicate that absorption of a photon by the Pfr state of PaBphP converts a light signal into a structural signal via twisting and untwisting of the methine bridges in the linear tetrapyrrole within the confined protein cavity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337037/" 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/PMC3337037/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Xiaojing -- Ren, Zhong -- Kuk, Jane -- Moffat, Keith -- GM036452/GM/NIGMS NIH HHS/ -- R01 GM036452/GM/NIGMS NIH HHS/ -- R01 GM036452-27/GM/NIGMS NIH HHS/ -- RR07707/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Oct 16;479(7373):428-32. doi: 10.1038/nature10506.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. xiaojingyang@uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22002602" target="_blank"〉PubMed〈/a〉
    Keywords: Absorption ; Biliverdine/chemistry/radiation effects ; Crystallography ; Isomerism ; Light ; Models, Molecular ; Phosphorylation ; Photochemical Processes/radiation effects ; Photons ; Phytochrome/*chemistry/*metabolism/radiation effects ; Protein Conformation/radiation effects ; Pseudomonas aeruginosa/*chemistry ; *Temperature ; Tetrapyrroles
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  • 88
    Publication Date: 2011-08-02
    Description: 'Florigen' was proposed 75 years ago to be synthesized in the leaf and transported to the shoot apex, where it induces flowering. Only recently have genetic and biochemical studies established that florigen is encoded by FLOWERING LOCUS T (FT), a gene that is universally conserved in higher plants. Nonetheless, the exact function of florigen during floral induction remains poorly understood and receptors for florigen have not been identified. Here we show that the rice FT homologue Hd3a interacts with 14-3-3 proteins in the apical cells of shoots, yielding a complex that translocates to the nucleus and binds to the Oryza sativa (Os)FD1 transcription factor, a rice homologue of Arabidopsis thaliana FD. The resultant ternary 'florigen activation complex' (FAC) induces transcription of OsMADS15, a homologue of A. thaliana APETALA1 (AP1), which leads to flowering. We have determined the 2.4 A crystal structure of rice FAC, which provides a mechanistic basis for florigen function in flowering. Our results indicate that 14-3-3 proteins act as intracellular receptors for florigen in shoot apical cells, and offer new approaches to manipulate flowering in various crops and trees.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Taoka, Ken-ichiro -- Ohki, Izuru -- Tsuji, Hiroyuki -- Furuita, Kyoko -- Hayashi, Kokoro -- Yanase, Tomoko -- Yamaguchi, Midori -- Nakashima, Chika -- Purwestri, Yekti Asih -- Tamaki, Shojiro -- Ogaki, Yuka -- Shimada, Chihiro -- Nakagawa, Atsushi -- Kojima, Chojiro -- Shimamoto, Ko -- England -- Nature. 2011 Jul 31;476(7360):332-5. doi: 10.1038/nature10272.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Plant Molecular Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21804566" target="_blank"〉PubMed〈/a〉
    Keywords: 14-3-3 Proteins/*metabolism ; *Arabidopsis Proteins/chemistry ; Calcium-Binding Proteins/chemistry ; Cell Nucleus/metabolism ; Flowers/*growth & development/*metabolism ; Gene Expression Regulation, Plant ; MADS Domain Proteins/chemistry ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Oryza/genetics/growth & development/*metabolism ; Plant Proteins/chemistry/genetics/*metabolism ; Plant Shoots/cytology ; Protein Binding ; Sequence Homology, Amino Acid ; Transcription Factors/chemistry ; Two-Hybrid System Techniques
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  • 89
    Publication Date: 2011-07-19
    Description: The chemical step of natural protein synthesis, peptide bond formation, is catalysed by the large subunit of the ribosome. Crystal structures have shown that the active site for peptide bond formation is composed entirely of RNA. Recent work has focused on how an RNA active site is able to catalyse this fundamental biological reaction at a suitable rate for protein synthesis. On the basis of the absence of important ribosomal functional groups, lack of a dependence on pH, and the dominant contribution of entropy to catalysis, it has been suggested that the role of the ribosome is limited to bringing the substrates into close proximity. Alternatively, the importance of the 2'-hydroxyl of the peptidyl-transfer RNA and a Bronsted coefficient near zero have been taken as evidence that the ribosome coordinates a proton-transfer network. Here we report the transition state of peptide bond formation, based on analysis of the kinetic isotope effect at five positions within the reaction centre of a peptidyl-transfer RNA mimic. Our results indicate that in contrast to the uncatalysed reaction, formation of the tetrahedral intermediate and proton transfer from the nucleophilic nitrogen both occur in the rate-limiting step. Unlike in previous proposals, the reaction is not fully concerted; instead, breakdown of the tetrahedral intermediate occurs in a separate fast step. This suggests that in addition to substrate positioning, the ribosome is contributing to chemical catalysis by changing the rate-limiting transition state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154986/" 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/PMC3154986/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hiller, David A -- Singh, Vipender -- Zhong, Minghong -- Strobel, Scott A -- GM54839/GM/NIGMS NIH HHS/ -- R01 GM054839/GM/NIGMS NIH HHS/ -- R01 GM054839-10/GM/NIGMS NIH HHS/ -- R01 GM054839-11/GM/NIGMS NIH HHS/ -- R01 GM054839-12/GM/NIGMS NIH HHS/ -- R01 GM054839-12S1/GM/NIGMS NIH HHS/ -- R01 GM054839-13/GM/NIGMS NIH HHS/ -- R01 GM054839-13S1/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jul 17;476(7359):236-9. doi: 10.1038/nature10248.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21765427" target="_blank"〉PubMed〈/a〉
    Keywords: *Biocatalysis ; Catalytic Domain ; Kinetics ; Models, Biological ; Models, Chemical ; Models, Molecular ; Organelle Biogenesis ; *Protein Biosynthesis ; Ribosomes/*chemistry/genetics/*metabolism ; Static Electricity
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  • 90
    Publication Date: 2011-11-05
    Description: Dryolestoids are an extinct mammalian group belonging to the lineage leading to modern marsupials and placentals. Dryolestoids are known by teeth and jaws from the Jurassic period of North America and Europe, but they thrived in South America up to the end of the Mesozoic era and survived to the beginnings of the Cenozoic. Isolated teeth and jaws from the latest Cretaceous of South America provide mounting evidence that, at least in western Gondwana, dryolestoids developed into strongly endemic groups by the Late Cretaceous. However, the lack of pre-Late Cretaceous dryolestoid remains made study of their origin and early diversification intractable. Here we describe the first mammalian remains from the early Late Cretaceous of South America, including two partial skulls and jaws of a derived dryolestoid showing dental and cranial features unknown among any other group of Mesozoic mammals, such as single-rooted molars preceded by double-rooted premolars, combined with a very long muzzle, exceedingly long canines and evidence of highly specialized masticatory musculature. On one hand, the new mammal shares derived features of dryolestoids with forms from the Jurassic of Laurasia, whereas on the other hand, it is very specialized and highlights the endemic, diverse dryolestoid fauna from the Cretaceous of South America. Our specimens include only the second mammalian skull known for the Cretaceous of Gondwana, bridging a previous 60-million-year gap in the fossil record, and document the whole cranial morphology of a dryolestoid, revealing an unsuspected morphological and ecological diversity for non-tribosphenic mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rougier, Guillermo W -- Apesteguia, Sebastian -- Gaetano, Leandro C -- England -- Nature. 2011 Nov 2;479(7371):98-102. doi: 10.1038/nature10591.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40202, USA. grougier@louisville.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22051679" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Extinction, Biological ; *Fossils ; Jaw/anatomy & histology ; Mammals/*anatomy & histology/classification ; Phylogeny ; Skull/*anatomy & histology ; South America ; Tooth/anatomy & histology
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  • 91
    Publication Date: 2011-12-20
    Description: Small multidrug resistance transporters provide an ideal system to study the minimal requirements for active transport. EmrE is one such transporter in Escherichia coli. It exports a broad class of polyaromatic cation substrates, thus conferring resistance to drug compounds matching this chemical description. However, a great deal of controversy has surrounded the topology of the EmrE homodimer. Here we show that asymmetric antiparallel EmrE exchanges between inward- and outward-facing states that are identical except that they have opposite orientation in the membrane. We quantitatively measure the global conformational exchange between these two states for substrate-bound EmrE in bicelles using solution NMR dynamics experiments. Forster resonance energy transfer reveals that the monomers within each dimer are antiparallel, and paramagnetic relaxation enhancement NMR experiments demonstrate differential water accessibility of the two monomers within each dimer. Our experiments reveal a 'dynamic symmetry' that reconciles the asymmetric EmrE structure with the functional symmetry of residues in the active site.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253143/" 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/PMC3253143/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morrison, Emma A -- DeKoster, Gregory T -- Dutta, Supratik -- Vafabakhsh, Reza -- Clarkson, Michael W -- Bahl, Arjun -- Kern, Dorothee -- Ha, Taekjip -- Henzler-Wildman, Katherine A -- 1R01GM095839/GM/NIGMS NIH HHS/ -- R01 GM095839/GM/NIGMS NIH HHS/ -- R01 GM095839-01A1/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Dec 18;481(7379):45-50. doi: 10.1038/nature10703.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22178925" target="_blank"〉PubMed〈/a〉
    Keywords: Antiporters/*chemistry/*metabolism ; Biological Transport ; Catalytic Domain ; Escherichia coli/*chemistry/metabolism ; Escherichia coli Proteins/*chemistry/*metabolism ; Fluorescence Resonance Energy Transfer ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Pharmaceutical Preparations/*metabolism ; Protein Conformation ; Protein Multimerization ; Water/chemistry
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  • 92
    Publication Date: 2011-12-06
    Description: High-conductance voltage- and Ca(2+)-activated K(+) channels function in many physiological processes that link cell membrane voltage and intracellular Ca(2+) concentration, including neuronal electrical activity, skeletal and smooth muscle contraction, and hair cell tuning. Like other voltage-dependent K(+) channels, Ca(2+)-activated K(+) channels open when the cell membrane depolarizes, but in contrast to other voltage-dependent K(+) channels, they also open when intracellular Ca(2+) concentrations rise. Channel opening by Ca(2+) is made possible by a structure called the gating ring, which is located in the cytoplasm. Recent structural studies have defined the Ca(2+)-free, closed, conformation of the gating ring, but the Ca(2+)-bound, open, conformation is not yet known. Here we present the Ca(2+)-bound conformation of the gating ring. This structure shows how one layer of the gating ring, in response to the binding of Ca(2+), opens like the petals of a flower. The degree to which it opens explains how Ca(2+) binding can open the transmembrane pore. These findings present a molecular basis for Ca(2+) activation of K(+) channels and suggest new possibilities for targeting the gating ring to treat conditions such as asthma and hypertension.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319005/" 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/PMC3319005/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Peng -- Leonetti, Manuel D -- Hsiung, Yichun -- MacKinnon, Roderick -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Dec 4;481(7379):94-7. doi: 10.1038/nature10670.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, Howard Hughes Medical Institute, 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/22139424" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/metabolism ; Calcium/*metabolism/pharmacology ; Conserved Sequence ; Crystallography, X-Ray ; Cytoplasm/metabolism ; *Electric Conductivity ; Humans ; Hypertension/metabolism ; *Ion Channel Gating/drug effects ; Large-Conductance Calcium-Activated Potassium Channels/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Pliability ; Protein Structure, Tertiary ; Zebrafish
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  • 93
    Publication Date: 2011-12-14
    Description: 3-Methylcrotonyl-CoA carboxylase (MCC), a member of the biotin-dependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglycinuria (MCG) and other serious diseases in humans. MCC has strong sequence conservation with propionyl-CoA carboxylase (PCC), and their holoenzymes are both 750-kilodalton (kDa) alpha(6)beta(6) dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are markedly different when compared to PCC. The alpha-subunits show trimeric association in the PaMCC holoenzyme, whereas they have no contacts with each other in PCC. Moreover, the positions of the two domains in the beta-subunit of PaMCC are swapped relative to those in PCC. This structural information establishes a foundation for understanding the disease-causing mutations of MCC and provides new insights into the catalytic mechanism and evolution of biotin-dependent carboxylases. The large structural differences between MCC and PCC also have general implications for the relationship between sequence conservation and structural similarity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271731/" 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/PMC3271731/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Christine S -- Ge, Peng -- Zhou, Z Hong -- Tong, Liang -- DK067238/DK/NIDDK NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- GM08281/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK067238/DK/NIDDK NIH HHS/ -- R01 DK067238-08/DK/NIDDK NIH HHS/ -- R01 GM071940/GM/NIGMS NIH HHS/ -- R01 GM071940-08/GM/NIGMS NIH HHS/ -- T32 GM008281/GM/NIGMS NIH HHS/ -- T32 GM008281-25/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Dec 11;481(7380):219-23. doi: 10.1038/nature10691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Columbia University, New York, New York 10027, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158123" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biocatalysis ; Carbon-Carbon Ligases/*chemistry/genetics/metabolism/ultrastructure ; Coenzyme A/chemistry/metabolism ; Crystallography, X-Ray ; Disease/genetics ; Holoenzymes/chemistry/metabolism ; Humans ; Methylmalonyl-CoA Decarboxylase/chemistry ; Models, Molecular ; Mutation/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/genetics/metabolism ; Pseudomonas aeruginosa/*enzymology
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  • 94
    Publication Date: 2011-12-20
    Description: Side chains of Lys/Arg near transmembrane domain (TMD) membrane-water interfaces can 'snorkel', placing their positive charge near negatively charged phospholipid head groups; however, snorkelling's functional effects are obscure. Integrin beta TMDs have such conserved basic amino acids. Here we use NMR spectroscopy to show that integrin beta(3)(Lys 716) helps determine beta(3) TMD topography. The alpha(IotaIotab)beta(3) TMD structure indicates that precise beta(3) TMD crossing angles enable the assembly of outer and inner membrane 'clasps' that hold the alphabeta TMD together to limit transmembrane signalling. Mutation of beta(3)(Lys 716) caused dissociation of alpha(IotaIotab)beta(3) TMDs and integrin activation. To confirm that altered topography of beta(3)(Lys 716) mutants activated alpha(IotaIotab)beta(3), we used directed evolution of beta(3)(K716A) to identify substitutions restoring default state. Introduction of Pro(711) at the midpoint of beta(3) TMD (A711P) increased alpha(IotaIotab)beta(3) TMD association and inactivated integrin alpha(IotaIotab)beta(3)(A711P,K716A). beta(3)(Pro 711) introduced a TMD kink of 30 +/- 1 degrees precisely at the border of the outer and inner membrane clasps, thereby decoupling the tilt between these segments. Thus, widely occurring snorkelling residues in TMDs can help maintain TMD topography and membrane-embedding, thereby regulating transmembrane signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257387/" 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/PMC3257387/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Chungho -- Schmidt, Thomas -- Cho, Eun-Gyung -- Ye, Feng -- Ulmer, Tobias S -- Ginsberg, Mark H -- AR27214/AR/NIAMS NIH HHS/ -- HL078784/HL/NHLBI NIH HHS/ -- HL089726/HL/NHLBI NIH HHS/ -- HL57900/HL/NHLBI NIH HHS/ -- P01 HL057900/HL/NHLBI NIH HHS/ -- P01 HL057900-14/HL/NHLBI NIH HHS/ -- P01 HL078784/HL/NHLBI NIH HHS/ -- P01 HL078784-08/HL/NHLBI NIH HHS/ -- R01 AR027214/AR/NIAMS NIH HHS/ -- R01 AR027214-31/AR/NIAMS NIH HHS/ -- R01 HL089726/HL/NHLBI NIH HHS/ -- R01 HL106489/HL/NHLBI NIH HHS/ -- R01 HL106489-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Dec 18;481(7380):209-13. doi: 10.1038/nature10697.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22178926" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; CHO Cells ; Cell Membrane/*metabolism ; Cricetinae ; Directed Molecular Evolution ; Genetic Complementation Test ; Integrins/*chemistry/genetics/*metabolism ; Lysine/*chemistry/genetics/*metabolism ; Membrane Lipids/metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Nuclear Magnetic Resonance, Biomolecular ; Pliability ; Proline/chemistry/genetics/metabolism ; Protein Binding ; Protein Multimerization ; Protein Stability ; Protein Structure, Tertiary ; *Signal Transduction
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  • 95
    Publication Date: 2011-07-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Horn, Richard -- England -- Nature. 2011 Jul 20;475(7356):305-6. doi: 10.1038/475305a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21776074" target="_blank"〉PubMed〈/a〉
    Keywords: Arcobacter/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; *Ion Channel Gating ; Ion Transport ; Models, Molecular ; Protein Conformation ; Sodium/metabolism ; Sodium Channels/*chemistry/*metabolism ; Structure-Activity Relationship
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  • 96
    Publication Date: 2011-06-17
    Description: Asparagine-linked glycosylation is a post-translational modification of proteins containing the conserved sequence motif Asn-X-Ser/Thr. The attachment of oligosaccharides is implicated in diverse processes such as protein folding and quality control, organism development or host-pathogen interactions. The reaction is catalysed by oligosaccharyltransferase (OST), a membrane protein complex located in the endoplasmic reticulum. The central, catalytic enzyme of OST is the STT3 subunit, which has homologues in bacteria and archaea. Here we report the X-ray structure of a bacterial OST, the PglB protein of Campylobacter lari, in complex with an acceptor peptide. The structure defines the fold of STT3 proteins and provides insight into glycosylation sequon recognition and amide nitrogen activation, both of which are prerequisites for the formation of the N-glycosidic linkage. We also identified and validated catalytically important, acidic amino acid residues. Our results provide the molecular basis for understanding the mechanism of N-linked glycosylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lizak, Christian -- Gerber, Sabina -- Numao, Shin -- Aebi, Markus -- Locher, Kaspar P -- England -- Nature. 2011 Jun 15;474(7351):350-5. doi: 10.1038/nature10151.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Microbiology, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677752" target="_blank"〉PubMed〈/a〉
    Keywords: Amides/metabolism ; Amino Acid Motifs ; Asparagine/chemistry/genetics/metabolism ; Campylobacter lari/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Glycosylation ; Hexosyltransferases/*chemistry/genetics/metabolism ; Membrane Proteins/*chemistry/genetics/metabolism ; Models, Molecular ; Nitrogen/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Substrate Specificity
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  • 97
    Publication Date: 2011-10-01
    Description: G protein-coupled receptors represent the largest family of membrane receptors that instigate signalling through nucleotide exchange on heterotrimeric G proteins. Nucleotide exchange, or more precisely, GDP dissociation from the G protein alpha-subunit, is the key step towards G protein activation and initiation of downstream signalling cascades. Despite a wealth of biochemical and biophysical studies on inactive and active conformations of several heterotrimeric G proteins, the molecular underpinnings of G protein activation remain elusive. To characterize this mechanism, we applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs (the stimulatory G protein for adenylyl cyclase) on formation of a complex with agonist-bound human beta(2) adrenergic receptor (beta(2)AR). Here we report structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the beta(2)AR-Gs complex. Together with X-ray crystallographic and electron microscopic data of the beta(2)AR-Gs complex (from refs 2, 3), we provide a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the alpha-subunit of Gs and consequently alters the 'P-loop' that binds the beta-phosphate in GDP. As with the Ras family of small-molecular-weight G proteins, P-loop stabilization and beta-phosphate coordination are key determinants of GDP (and GTP) binding affinity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448949/" 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/PMC3448949/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chung, Ka Young -- Rasmussen, Soren G F -- Liu, Tong -- Li, Sheng -- DeVree, Brian T -- Chae, Pil Seok -- Calinski, Diane -- Kobilka, Brian K -- Woods, Virgil L Jr -- Sunahara, Roger K -- AI076961/AI/NIAID NIH HHS/ -- AI081982/AI/NIAID NIH HHS/ -- AI2008031/AI/NIAID NIH HHS/ -- CA118595/CA/NCI NIH HHS/ -- GM008270/GM/NIGMS NIH HHS/ -- GM066170/GM/NIGMS NIH HHS/ -- GM068603/GM/NIGMS NIH HHS/ -- GM083118/GM/NIGMS NIH HHS/ -- GM093325/GM/NIGMS NIH HHS/ -- GM20501/GM/NIGMS NIH HHS/ -- HL071078/HL/NHLBI NIH HHS/ -- NS28471/NS/NINDS NIH HHS/ -- P60DK-20572/DK/NIDDK NIH HHS/ -- R01 GM020501/GM/NIGMS NIH HHS/ -- R01 GM068603/GM/NIGMS NIH HHS/ -- R01 GM068603-03/GM/NIGMS NIH HHS/ -- R01 GM068603-04/GM/NIGMS NIH HHS/ -- R01 GM068603-05/GM/NIGMS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 GM083118-02/GM/NIGMS NIH HHS/ -- R01 GM083118-03/GM/NIGMS NIH HHS/ -- R01 GM083118-04/GM/NIGMS NIH HHS/ -- RR029388/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Sep 28;477(7366):611-5. doi: 10.1038/nature10488.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21956331" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor Agonists/chemistry/metabolism ; Animals ; Biocatalysis ; Catalytic Domain ; Cattle ; Crystallography, X-Ray ; Deuterium Exchange Measurement ; GTP-Binding Protein alpha Subunits, Gs/*chemistry/*metabolism/ultrastructure ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism/ultrastructure
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  • 98
    Publication Date: 2011-07-02
    Description: Prochlorococcus cyanobacteria are extremely abundant in the oceans, as are the viruses that infect them. How hosts and viruses coexist in nature remains unclear, although the presence of both susceptible and resistant cells may allow this coexistence. Combined whole-genome sequencing and PCR screening technology now enables us to investigate the effect of resistance on genome evolution and the genomic mechanisms behind the long-term coexistence of Prochlorococcus and their viruses. Here we present a genome analysis of 77 substrains selected for resistance to ten viruses, revealing mutations primarily in non-conserved, horizontally transferred genes that localize to a single hypervariable genomic island. Mutations affected viral attachment to the cell surface and imposed a fitness cost to the host, manifested by significantly lower growth rates or a previously unknown mechanism of more rapid infection by other viruses. The mutant genes are generally uncommon in nature yet some carry polymorphisms matching those found experimentally. These data are empirical evidence indicating that viral-attachment genes are preferentially located in genomic islands and that viruses are a selective pressure enhancing the diversity of both island genes and island gene content. This diversity emerges as a genomic mechanism that reduces the effective host population size for infection by a given virus, thus facilitating long-term coexistence between viruses and their hosts in nature.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Avrani, Sarit -- Wurtzel, Omri -- Sharon, Itai -- Sorek, Rotem -- Lindell, Debbie -- England -- Nature. 2011 Jun 29;474(7353):604-8. doi: 10.1038/nature10172.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21720364" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Evolution, Molecular ; Genes, Bacterial/genetics ; *Genetic Variation ; Genome, Bacterial ; Genomic Islands/*genetics ; Genotype ; Molecular Sequence Data ; Mutation ; Phylogeny ; Podoviridae/*physiology ; Prochlorococcus/classification/*genetics/*virology ; Virus Attachment
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 99
    Publication Date: 2011-02-15
    Description: The TrkH/TrkG/KtrB proteins mediate K(+) uptake in bacteria and probably evolved from simple K(+) channels by multiple gene duplications or fusions. Here we present the crystal structure of a TrkH from Vibrio parahaemolyticus. TrkH is a homodimer, and each protomer contains an ion permeation pathway. A selectivity filter, similar in architecture to those of K(+) channels but significantly shorter, is lined by backbone and side-chain oxygen atoms. Functional studies showed that TrkH is selective for permeation of K(+) and Rb(+) over smaller ions such as Na(+) or Li(+). Immediately intracellular to the selectivity filter are an intramembrane loop and an arginine residue, both highly conserved, which constrict the permeation pathway. Substituting the arginine with an alanine significantly increases the rate of K(+) flux. These results reveal the molecular basis of K(+) selectivity and suggest a novel gating mechanism for this large and important family of membrane transport proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077569/" 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/PMC3077569/" 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 -- Jin, Xiangshu -- Huang, Hua -- Derebe, Mehabaw Getahun -- Levin, Elena J -- Kabaleeswaran, Venkataraman -- Pan, Yaping -- Punta, Marco -- Love, James -- Weng, Jun -- Quick, Matthias -- Ye, Sheng -- Kloss, Brian -- Bruni, Renato -- Martinez-Hackert, Erik -- Hendrickson, Wayne A -- Rost, Burkhard -- Javitch, Jonathan A -- Rajashankar, Kanagalaghatta R -- Jiang, Youxing -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM05026/GM/NIGMS NIH HHS/ -- GM05026-SUB0007/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- K05 DA022413/DA/NIDA NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 DK088057-01/DK/NIDDK NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01 HL086392-05/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):336-40. doi: 10.1038/nature09731. Epub 2011 Feb 13.〈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/21317882" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Amino Acid Sequence ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry ; Ion Channel Gating ; Ion Transport ; Models, Molecular ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Vibrio parahaemolyticus/*chemistry
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
    Publication Date: 2011-09-02
    Description: The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments. Among amniotes, genome sequences are available for mammals and birds, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes. Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184186/" 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/PMC3184186/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alfoldi, Jessica -- Di Palma, Federica -- Grabherr, Manfred -- Williams, Christina -- Kong, Lesheng -- Mauceli, Evan -- Russell, Pamela -- Lowe, Craig B -- Glor, Richard E -- Jaffe, Jacob D -- Ray, David A -- Boissinot, Stephane -- Shedlock, Andrew M -- Botka, Christopher -- Castoe, Todd A -- Colbourne, John K -- Fujita, Matthew K -- Moreno, Ricardo Godinez -- ten Hallers, Boudewijn F -- Haussler, David -- Heger, Andreas -- Heiman, David -- Janes, Daniel E -- Johnson, Jeremy -- de Jong, Pieter J -- Koriabine, Maxim Y -- Lara, Marcia -- Novick, Peter A -- Organ, Chris L -- Peach, Sally E -- Poe, Steven -- Pollock, David D -- de Queiroz, Kevin -- Sanger, Thomas -- Searle, Steve -- Smith, Jeremy D -- Smith, Zachary -- Swofford, Ross -- Turner-Maier, Jason -- Wade, Juli -- Young, Sarah -- Zadissa, Amonida -- Edwards, Scott V -- Glenn, Travis C -- Schneider, Christopher J -- Losos, Jonathan B -- Lander, Eric S -- Breen, Matthew -- Ponting, Chris P -- Lindblad-Toh, Kerstin -- BB/F007590/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U137761446/Medical Research Council/United Kingdom -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-08/HG/NHGRI NIH HHS/ -- England -- Nature. 2011 Aug 31;477(7366):587-91. doi: 10.1038/nature10390.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. jalfoldi@broadinstitute.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21881562" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/*genetics ; Chickens/genetics ; *Evolution, Molecular ; GC Rich Sequence/genetics ; Genome/*genetics ; Genomics ; Humans ; Lizards/*genetics ; Mammals/*genetics ; Molecular Sequence Data ; Phylogeny ; Synteny/genetics ; X Chromosome/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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