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  • Binding Sites  (2)
  • Influenza A Virus, H5N1 Subtype/*enzymology  (2)
  • Nature Publishing Group (NPG)  (3)
  • 1
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    Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-11
    Description: The recent emergence of highly pathogenic avian influenza A virus strains with subtype H5N1 pose a global threat to human health. Elucidation of the underlying mechanisms of viral replication is critical for development of anti-influenza virus drugs. The influenza RNA-dependent RNA polymerase (RdRp) heterotrimer has crucial roles in viral RNA replication and transcription. It contains three proteins: PA, PB1 and PB2. PB1 harbours polymerase and endonuclease activities and PB2 is responsible for cap binding; PA is implicated in RNA replication and proteolytic activity, although its function is less clearly defined. Here we report the 2.9 angstrom structure of avian H5N1 influenza A virus PA (PA(C), residues 257-716) in complex with the PA-binding region of PB1 (PB1(N), residues 1-25). PA(C) has a fold resembling a dragon's head with PB1(N) clamped into its open 'jaws'. PB1(N) is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1(N) to PA(C) at the atomic level, demonstrating a potential target for novel anti-influenza therapeutics. We also discuss a potential nucleotide binding site and the roles of some known residues involved in polymerase activity. Furthermore, to explore the role of PA in viral replication and transcription, we propose a model for the influenza RdRp heterotrimer by comparing PA(C) with the lambda3 reovirus polymerase structure, and docking the PA(C) structure into an available low resolution electron microscopy map.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Xiaojing -- Zhou, Jie -- Bartlam, Mark -- Zhang, Rongguang -- Ma, Jianyuan -- Lou, Zhiyong -- Li, Xuemei -- Li, Jingjing -- Joachimiak, Andrzej -- Zeng, Zonghao -- Ge, Ruowen -- Rao, Zihe -- Liu, Yingfang -- England -- Nature. 2008 Aug 28;454(7208):1123-6. doi: 10.1038/nature07120. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Birds/*virology ; Crystallography, X-Ray ; Influenza A Virus, H5N1 Subtype/*enzymology ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism ; Nucleotides/metabolism ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Protein Structure, Quaternary ; RNA Replicase/*chemistry/metabolism ; Viral Proteins/*chemistry/*metabolism ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The heterotrimeric influenza virus polymerase, containing the PA, PB1 and PB2 proteins, catalyses viral RNA replication and transcription in the nucleus of infected cells. PB1 holds the polymerase active site and reportedly harbours endonuclease activity, whereas PB2 is responsible for cap binding. The PA amino terminus is understood to be the major functional part of the PA protein and has been implicated in several roles, including endonuclease and protease activities as well as viral RNA/complementary RNA promoter binding. Here we report the 2.2 angstrom (A) crystal structure of the N-terminal 197 residues of PA, termed PA(N), from an avian influenza H5N1 virus. The PA(N) structure has an alpha/beta architecture and reveals a bound magnesium ion coordinated by a motif similar to the (P)DX(N)(D/E)XK motif characteristic of many endonucleases. Structural comparisons and mutagenesis analysis of the motif identified in PA(N) provide further evidence that PA(N) holds an endonuclease active site. Furthermore, functional analysis with in vivo ribonucleoprotein reconstitution and direct in vitro endonuclease assays strongly suggest that PA(N) holds the endonuclease active site and has critical roles in endonuclease activity of the influenza virus polymerase, rather than PB1. The high conservation of this endonuclease active site among influenza strains indicates that PA(N) is an important target for the design of new anti-influenza therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Puwei -- Bartlam, Mark -- Lou, Zhiyong -- Chen, Shoudeng -- Zhou, Jie -- He, Xiaojing -- Lv, Zongyang -- Ge, Ruowen -- Li, Xuemei -- Deng, Tao -- Fodor, Ervin -- Rao, Zihe -- Liu, Yingfang -- G0700848/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):909-13. doi: 10.1038/nature07720. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194458" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/virology ; Catalytic Domain ; Crystallography, X-Ray ; Endonucleases/*chemistry/genetics/*metabolism ; Influenza A Virus, H5N1 Subtype/*enzymology ; Influenza in Birds/*virology ; Models, Molecular ; Protein Subunits/chemistry/genetics/metabolism ; RNA Replicase/*chemistry/genetics/*metabolism ; Viral Proteins/*chemistry/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Structure of a cation-bound multidrug and toxic compound extrusion transporter (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-24
    Description: Transporter proteins from the MATE (multidrug and toxic compound extrusion) family are vital in metabolite transport in plants, directly affecting crop yields worldwide. MATE transporters also mediate multiple-drug resistance (MDR) in bacteria and mammals, modulating the efficacy of many pharmaceutical drugs used in the treatment of a variety of diseases. MATE transporters couple substrate transport to electrochemical gradients and are the only remaining class of MDR transporters whose structure has not been determined. Here we report the X-ray structure of the MATE transporter NorM from Vibrio cholerae determined to 3.65 A, revealing an outward-facing conformation with two portals open to the outer leaflet of the membrane and a unique topology of the predicted 12 transmembrane helices distinct from any other known MDR transporter. We also report a cation-binding site in close proximity to residues previously deemed critical for transport. This conformation probably represents a stage of the transport cycle with high affinity for monovalent cations and low affinity for substrates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152480/" 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/PMC3152480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Xiao -- Szewczyk, Paul -- Karyakin, Andrey -- Evin, Mariah -- Hong, Wen-Xu -- Zhang, Qinghai -- Chang, Geoffrey -- GM70480/GM/NIGMS NIH HHS/ -- GM73197/GM/NIGMS NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-07/GM/NIGMS NIH HHS/ -- R01 GM070480/GM/NIGMS NIH HHS/ -- R01 GM070480-01A1/GM/NIGMS NIH HHS/ -- R01 GM070480-02/GM/NIGMS NIH HHS/ -- R01 GM070480-03/GM/NIGMS NIH HHS/ -- R01 GM070480-04/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):991-4. doi: 10.1038/nature09408. Epub 2010 Sep 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20861838" target="_blank"〉PubMed〈/a〉
    Keywords: Antiporters/*chemistry/genetics/*metabolism ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Cations/chemistry/metabolism ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Ion Transport ; Models, Molecular ; Protein Conformation ; Reproducibility of Results ; Static Electricity ; Substrate Specificity ; Vibrio cholerae/*chemistry
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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