Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors
Identifieur interne : 000438 ( Pmc/Curation ); précédent : 000437; suivant : 000439Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors
Auteurs : Robert N. Kirchdoerfer ; Andrew B. WardSource :
- Nature Communications [ 2041-1723 ] ; 2019.
Abstract
Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.
Url:
DOI: 10.1038/s41467-019-10280-3
PubMed: 31138817
PubMed Central: 6538669
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Ward</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31138817</idno><idno type="pmc">6538669</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538669</idno><idno type="RBID">PMC:6538669</idno><idno type="doi">10.1038/s41467-019-10280-3</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000438</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000438</idno><idno type="wicri:Area/Pmc/Curation">000438</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000438</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors</title><author><name sortKey="Kirchdoerfer, Robert N" sort="Kirchdoerfer, Robert N" uniqKey="Kirchdoerfer R" first="Robert N." last="Kirchdoerfer">Robert N. Kirchdoerfer</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Ward, Andrew B" sort="Ward, Andrew B" uniqKey="Ward A" first="Andrew B." last="Ward">Andrew B. Ward</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31138817</article-id><article-id pub-id-type="pmc">6538669</article-id><article-id pub-id-type="publisher-id">10280</article-id><article-id pub-id-type="doi">10.1038/s41467-019-10280-3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5974-2709</contrib-id><name><surname>Kirchdoerfer</surname><given-names>Robert N.</given-names></name><address><email>rkirchdo@scripps.edu</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-7153-3769</contrib-id><name><surname>Ward</surname><given-names>Andrew B.</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122199231</institution-id><institution-id institution-id-type="GRID">grid.214007.0</institution-id><institution>Department of Integrative Structural and Computational Biology,</institution><institution>The Scripps Research Institute,</institution></institution-wrap>10550 North Torrey Pines Road, HZ-102, La Jolla, CA 92037 USA</aff></contrib-group><pub-date pub-type="epub"><day>28</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>28</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>2342</elocation-id><history><date date-type="received"><day>21</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>2</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.</p></abstract><abstract id="Abs2" abstract-type="web-summary"><p id="Par2">The pathogenic human coronaviruses SARS- and MERS-CoV can cause severe respiratory disease. Here the authors present the 3.1Å cryo-EM structure of the SARS-CoV RNA polymerase nsp12 bound to its essential co-factors nsp7 and nsp8, which is of interest for antiviral drug development.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Cryoelectron microscopy</kwd><kwd>SARS virus</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000060</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution></institution-wrap></funding-source><award-id>AI123498</award-id><award-id>AI127521</award-id><principal-award-recipient><name><surname>Kirchdoerfer</surname><given-names>Robert N.</given-names></name><name><surname>Ward</surname><given-names>Andrew B.</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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