Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design
Identifieur interne : 000432 ( Pmc/Curation ); précédent : 000431; suivant : 000433Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design
Auteurs : Fenghua Wang [République populaire de Chine] ; Cheng Chen [République populaire de Chine] ; Wenjie Tan [République populaire de Chine] ; Kailin Yang [États-Unis] ; Haitao Yang [République populaire de Chine]Source :
- Scientific Reports [ 2045-2322 ] ; 2016.
Abstract
First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (Mpro), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, Mpro has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 Mpro in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with Mpros from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 Mpro provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.
The online version of this article (doi:10.1038/srep22677) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1038/srep22677
PubMed: 26948040
PubMed Central: 4780191
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last="Wang">Fenghua Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.33763.32</institution-id><institution-id institution-id-type="ISNI">0000 0004 1761 2484</institution-id><institution>School of Life Sciences, Tianjin University,</institution></institution-wrap>Tianjin, 300072 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Cheng" sort="Chen, Cheng" uniqKey="Chen C" first="Cheng" last="Chen">Cheng Chen</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.33763.32</institution-id><institution-id institution-id-type="ISNI">0000 0004 1761 2484</institution-id><institution>School of Life Sciences, Tianjin University,</institution></institution-wrap>Tianjin, 300072 China</nlm:aff><country xml:lang="fr">République populaire de 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when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (M<sup>pro</sup>), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, M<sup>pro</sup> has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 M<sup>pro</sup> in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with M<sup>pro</sup>s from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 M<sup>pro</sup> provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1038/srep22677) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weiss, Sr" uniqKey="Weiss S">SR Weiss</name></author><author><name sortKey="Navas Martin, S" uniqKey="Navas Martin S">S Navas-Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Masters, Ps" uniqKey="Masters P">PS Masters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Siddell, S" uniqKey="Siddell 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</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">26948040</article-id><article-id pub-id-type="pmc">4780191</article-id><article-id pub-id-type="publisher-id">BFsrep22677</article-id><article-id pub-id-type="doi">10.1038/srep22677</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Wang</surname><given-names>Fenghua</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Chen</surname><given-names>Cheng</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Wenjie</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Kailin</given-names></name><address><email>yangk2@ccf.org</email></address><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Haitao</given-names></name><address><email>yanght@tju.edu.cn</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.33763.32</institution-id><institution-id institution-id-type="ISNI">0000 0004 1761 2484</institution-id><institution>School of Life Sciences, Tianjin University,</institution></institution-wrap>Tianjin, 300072 China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.488175.7</institution-id><institution>Tianjin International Joint Academy of Biotechnology and Medicine,</institution></institution-wrap>Tianjin, 300457 China</aff><aff id="Aff3"><label>3</label>Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206 China</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.254293.b</institution-id><institution-id institution-id-type="ISNI">0000 0004 0435 0569</institution-id><institution>Cleveland Clinic Lerner College of Medicine of Case Western Reserve University,</institution></institution-wrap>Cleveland, 44195 OH USA</aff></contrib-group><pub-date pub-type="epub"><day>7</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>7</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>6</volume><elocation-id>22677</elocation-id><history><date date-type="received"><day>4</day><month>12</month><year>2015</year></date><date date-type="accepted"><day>17</day><month>2</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s) 2016</copyright-statement><license license-type="OpenAccess"><license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. 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>First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (M<sup>pro</sup>), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, M<sup>pro</sup> has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 M<sup>pro</sup> in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with M<sup>pro</sup>s from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 M<sup>pro</sup> provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1038/srep22677) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Virology</kwd><kwd>X-ray crystallography</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2016</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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