The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor
Identifieur interne : 001773 ( Pmc/Checkpoint ); précédent : 001772; suivant : 001774The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor
Auteurs : Haitao Yang [République populaire de Chine] ; Maojun Yang [République populaire de Chine] ; Yi Ding [République populaire de Chine] ; Yiwei Liu [République populaire de Chine] ; Zhiyong Lou [République populaire de Chine] ; Zhe Zhou [République populaire de Chine] ; Lei Sun [République populaire de Chine] ; Lijuan Mo [République populaire de Chine] ; Sheng Ye [République populaire de Chine] ; Hai Pang [République populaire de Chine] ; George F. Gao [République populaire de Chine] ; Kanchan Anand [Allemagne] ; Mark Bartlam [République populaire de Chine] ; Rolf Hilgenfeld [Allemagne] ; Zihe Rao [République populaire de Chine]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2003.
Abstract
A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is the etiological agent responsible for the outbreak of SARS. The SARS-CoV main protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays a pivotal role in mediating viral replication and transcription functions through extensive proteolytic processing of two replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the SARS-CoV main protease at different pH values and in complex with a specific inhibitor. The protease structure has a fold that can be described as an augmented serine-protease, but with a Cys-His at the active site. This series of crystal structures, which is the first, to our knowledge, of any protein from the SARS virus, reveal substantial pH-dependent conformational changes, and an unexpected mode of inhibitor binding, providing a structural basis for rational drug design.
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DOI: 10.1073/pnas.1835675100
PubMed: 14585926
PubMed Central: 263746
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and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Sun, Lei" sort="Sun, Lei" uniqKey="Sun L" first="Lei" last="Sun">Lei Sun</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Mo, Lijuan" sort="Mo, Lijuan" uniqKey="Mo L" first="Lijuan" last="Mo">Lijuan Mo</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Pang, Hai" sort="Pang, Hai" uniqKey="Pang H" first="Hai" last="Pang">Hai Pang</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Anand, Kanchan" sort="Anand, Kanchan" uniqKey="Anand K" first="Kanchan" last="Anand">Kanchan Anand</name><affiliation wicri:level="1"><nlm:aff id="N0xa0e89f0.0x992f7d8">Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Lübeck, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Bartlam, Mark" sort="Bartlam, Mark" uniqKey="Bartlam M" first="Mark" last="Bartlam">Mark Bartlam</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><nlm:aff id="N0xa0e89f0.0x992f7d8">Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Lübeck, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">14585926</idno><idno type="pmc">263746</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC263746</idno><idno type="RBID">PMC:263746</idno><idno type="doi">10.1073/pnas.1835675100</idno><date when="2003">2003</date><idno type="wicri:Area/Pmc/Corpus">000741</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000741</idno><idno type="wicri:Area/Pmc/Curation">000741</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000741</idno><idno type="wicri:Area/Pmc/Checkpoint">001773</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">001773</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor</title><author><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Yang, Maojun" sort="Yang, Maojun" uniqKey="Yang M" first="Maojun" last="Yang">Maojun Yang</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Ding, Yi" sort="Ding, Yi" uniqKey="Ding Y" first="Yi" last="Ding">Yi Ding</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Liu, Yiwei" sort="Liu, Yiwei" uniqKey="Liu Y" first="Yiwei" last="Liu">Yiwei Liu</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Lou, Zhiyong" sort="Lou, Zhiyong" uniqKey="Lou Z" first="Zhiyong" last="Lou">Zhiyong Lou</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhou, Zhe" sort="Zhou, Zhe" uniqKey="Zhou Z" first="Zhe" last="Zhou">Zhe Zhou</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Sun, Lei" sort="Sun, Lei" uniqKey="Sun L" first="Lei" last="Sun">Lei Sun</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Mo, Lijuan" sort="Mo, Lijuan" uniqKey="Mo L" first="Lijuan" last="Mo">Lijuan Mo</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Pang, Hai" sort="Pang, Hai" uniqKey="Pang H" first="Hai" last="Pang">Hai Pang</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Anand, Kanchan" sort="Anand, Kanchan" uniqKey="Anand K" first="Kanchan" last="Anand">Kanchan Anand</name><affiliation wicri:level="1"><nlm:aff id="N0xa0e89f0.0x992f7d8">Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Lübeck, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Bartlam, Mark" sort="Bartlam, Mark" uniqKey="Bartlam M" first="Mark" last="Bartlam">Mark Bartlam</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><nlm:aff id="N0xa0e89f0.0x992f7d8">Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Lübeck, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0xa0e89f0.0x992f7d8">Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2003">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is the etiological agent responsible for the outbreak of SARS. The SARS-CoV main protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays a pivotal role in mediating viral replication and transcription functions through extensive proteolytic processing of two replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the SARS-CoV main protease at different pH values and in complex with a specific inhibitor. The protease structure has a fold that can be described as an augmented serine-protease, but with a Cys-His at the active site. This series of crystal structures, which is the first, to our knowledge, of any protein from the SARS virus, reveal substantial pH-dependent conformational changes, and an unexpected mode of inhibitor binding, providing a structural basis for rational drug design.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="publisher-id">pnas</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">14585926</article-id><article-id pub-id-type="pmc">263746</article-id><article-id pub-id-type="publisher-id">10013190</article-id><article-id pub-id-type="doi">10.1073/pnas.1835675100</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biochemistry</subject></subj-group></subj-group></article-categories><title-group><article-title>The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Haitao</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref><xref ref-type="fn" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Maojun</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref><xref ref-type="fn" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Ding</surname><given-names>Yi</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref><xref ref-type="fn" rid="fn1">†</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Yiwei</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Lou</surname><given-names>Zhiyong</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Zhe</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Lei</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Mo</surname><given-names>Lijuan</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Ye</surname><given-names>Sheng</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Pang</surname><given-names>Hai</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>George F.</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Anand</surname><given-names>Kanchan</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">‡</xref></contrib><contrib contrib-type="author"><name><surname>Bartlam</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref></contrib><contrib contrib-type="author"><name><surname>Hilgenfeld</surname><given-names>Rolf</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">‡</xref></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Zihe</given-names></name><xref ref-type="aff" rid="N0xa0e89f0.0x992f7d8">*</xref><xref ref-type="corresp" rid="cor1">§</xref></contrib></contrib-group><aff id="N0xa0e89f0.0x992f7d8"><label>*</label>Laboratory of Structural Biology, Tsinghua University and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, 100084 Beijing, China; and<label>‡</label>Institute of Biochemistry, University of Lübeck, 23538 Lübeck, Germany</aff><author-notes><fn id="cor1"><label>§</label><p> To whom correspondence should be addressed at: Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. E-mail: <email>raozh@xtal.tsinghua.edu.cn</email>. </p></fn><fn id="fn1"><label>†</label><p>H.Y., M.Y., and Y.D. contributed equally to this work.</p></fn><fn><p>Communicated by Brian W. Matthews, University of Oregon, Eugene, OR, September 8, 2003</p></fn></author-notes><pub-date pub-type="ppub"><day>11</day><month>11</month><year>2003</year></pub-date><pub-date pub-type="epub"><day>29</day><month>10</month><year>2003</year></pub-date><volume>100</volume><issue>23</issue><fpage>13190</fpage><lpage>13195</lpage><history><date date-type="received"><day>25</day><month>8</month><year>2003</year></date></history><copyright-statement>Copyright © 2003, The National Academy of Sciences</copyright-statement><copyright-year>2003</copyright-year><abstract><p>A newly identified severe acute respiratory syndrome coronavirus (SARS-CoV), is the etiological agent responsible for the outbreak of SARS. The SARS-CoV main protease, which is a 33.8-kDa protease (also called the 3C-like protease), plays a pivotal role in mediating viral replication and transcription functions through extensive proteolytic processing of two replicase polyproteins, pp1a (486 kDa) and pp1ab (790 kDa). Here, we report the crystal structures of the SARS-CoV main protease at different pH values and in complex with a specific inhibitor. The protease structure has a fold that can be described as an augmented serine-protease, but with a Cys-His at the active site. This series of crystal structures, which is the first, to our knowledge, of any protein from the SARS virus, reveal substantial pH-dependent conformational changes, and an unexpected mode of inhibitor binding, providing a structural basis for rational drug design.</p></abstract></article-meta><notes><fn-group><fn><p>Abbreviations: SARS, severe acute respiratory syndrome; CoV, coronavirus; HcoV, human CoV; Mpro, main protease; TGEV, porcine transmissible gastroenteritis virus; PEG, polyethylene glycol; CMK, chloromethyl ketone; N-finger, N-terminal residues 1-7.</p></fn><fn><p>Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, <ext-link ext-link-type="uri" xlink:href="www.rcsb.org">www.rcsb.org</ext-link> [PDB ID codes 1UJ1, 1UK3, 1UK2 (SARS-CoV Mpro, apoenzyme at pH 6.0, 7.6, and 8.0, respectively), and 1UK4 (SARS-CoV Mpro in complex with the hexapeptidyl CMK inhibitor].</p></fn></fn-group></notes></front></pmc><affiliations><list><country><li>Allemagne</li><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name></noRegion><name sortKey="Bartlam, Mark" sort="Bartlam, Mark" uniqKey="Bartlam M" first="Mark" last="Bartlam">Mark Bartlam</name><name sortKey="Ding, Yi" sort="Ding, Yi" uniqKey="Ding Y" first="Yi" last="Ding">Yi Ding</name><name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name><name sortKey="Liu, Yiwei" sort="Liu, Yiwei" uniqKey="Liu Y" first="Yiwei" last="Liu">Yiwei Liu</name><name sortKey="Lou, Zhiyong" sort="Lou, Zhiyong" uniqKey="Lou Z" first="Zhiyong" last="Lou">Zhiyong Lou</name><name sortKey="Mo, Lijuan" sort="Mo, Lijuan" uniqKey="Mo L" first="Lijuan" last="Mo">Lijuan Mo</name><name sortKey="Pang, Hai" sort="Pang, Hai" uniqKey="Pang H" first="Hai" last="Pang">Hai Pang</name><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><name sortKey="Sun, Lei" sort="Sun, Lei" uniqKey="Sun L" first="Lei" last="Sun">Lei Sun</name><name sortKey="Yang, Maojun" sort="Yang, Maojun" uniqKey="Yang M" first="Maojun" last="Yang">Maojun Yang</name><name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name><name sortKey="Zhou, Zhe" sort="Zhou, Zhe" uniqKey="Zhou Z" first="Zhe" last="Zhou">Zhe Zhou</name></country><country name="Allemagne"><noRegion><name sortKey="Anand, Kanchan" sort="Anand, Kanchan" uniqKey="Anand K" first="Kanchan" last="Anand">Kanchan Anand</name></noRegion><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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