Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design
Identifieur interne : 000826 ( Main/Exploration ); précédent : 000825; suivant : 000827Structure 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.
Url:
DOI: 10.1038/srep22677
PubMed: 26948040
PubMed Central: 4780191
Affiliations:
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last="Chen">Cheng Chen</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>School of Life Sciences, Tianjin University</institution>, Tianjin 300072,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Tianjin International Joint Academy of Biotechnology and Medicine</institution>, Tianjin 300457,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention</institution>, Beijing 102206,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Kailin" sort="Yang, Kailin" uniqKey="Yang K" first="Kailin" last="Yang">Kailin Yang</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Cleveland Clinic Lerner College of Medicine of Case Western Reserve University</institution>, Cleveland, OH 44195,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>School of Life Sciences, Tianjin University</institution>, Tianjin 300072,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Tianjin International Joint Academy of Biotechnology and Medicine</institution>, Tianjin 300457,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date 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></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weiss, S R" uniqKey="Weiss S">S. R. 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, P S" uniqKey="Masters P">P. S. Masters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Siddell, S" uniqKey="Siddell S">S. Siddell</name></author><author><name sortKey="Wege, H" uniqKey="Wege H">H. 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Minor</name></author><author><name sortKey="Carter, C W" uniqKey="Carter C">C. W. Carter</name></author><author><name sortKey="Sweet, R M" uniqKey="Sweet R">R. M. Sweet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccoy, A J" uniqKey="Mccoy A">A. J. McCoy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Emsley, P" uniqKey="Emsley P">P. Emsley</name></author><author><name sortKey="Cowtan, K" uniqKey="Cowtan K">K. Cowtan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, P D" uniqKey="Adams P">P. D. Adams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Larkin, M A" uniqKey="Larkin M">M. A. Larkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Robert, X" uniqKey="Robert X">X. Robert</name></author><author><name sortKey="Gouet, P" uniqKey="Gouet P">P. Gouet</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Fenghua" sort="Wang, Fenghua" uniqKey="Wang F" first="Fenghua" last="Wang">Fenghua Wang</name></noRegion><name sortKey="Chen, Cheng" sort="Chen, Cheng" uniqKey="Chen C" first="Cheng" last="Chen">Cheng Chen</name><name sortKey="Chen, Cheng" sort="Chen, Cheng" uniqKey="Chen C" first="Cheng" last="Chen">Cheng Chen</name><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name></country><country name="États-Unis"><noRegion><name sortKey="Yang, Kailin" sort="Yang, Kailin" uniqKey="Yang K" first="Kailin" last="Yang">Kailin Yang</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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