Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features
Identifieur interne : 001108 ( Pmc/Checkpoint ); précédent : 001107; suivant : 001109Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features
Auteurs : Jian Lei [Allemagne] ; Jeroen R. Mesters [Allemagne] ; Christian Drosten [Allemagne] ; Stefan Anemüller [Allemagne] ; Qingjun Ma [Allemagne] ; Rolf Hilgenfeld [Allemagne]Source :
- Antiviral Research [ 0166-3542 ] ; 2014.
Abstract
The 3D structure of the MERS-CoV papain-like protease (PLpro) has been determined. The enzyme has a deficient oxyanion hole and unique S3 as well as S5 subsites. Restoring the oxyanion hole through mutagenesis enhances the enzyme kinetics. The unique features of the enzyme will allow design of MERS-specific antivirals.
Url:
DOI: 10.1016/j.antiviral.2014.06.011
PubMed: 24992731
PubMed Central: 7113875
Affiliations:
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Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></affiliation></author><author><name sortKey="Mesters, Jeroen R" sort="Mesters, Jeroen R" uniqKey="Mesters J" first="Jeroen R." last="Mesters">Jeroen R. Mesters</name><affiliation wicri:level="1"><nlm:aff id="af005">Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="3"><nlm:aff id="af010">Institute of Virology, University of Bonn Medical School, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical School, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></affiliation></author><author><name sortKey="Anemuller, Stefan" sort="Anemuller, Stefan" uniqKey="Anemuller S" first="Stefan" last="Anemüller">Stefan Anemüller</name><affiliation wicri:level="1"><nlm:aff id="af005">Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></affiliation></author><author><name sortKey="Ma, Qingjun" sort="Ma, Qingjun" uniqKey="Ma Q" first="Qingjun" last="Ma">Qingjun Ma</name><affiliation wicri:level="1"><nlm:aff id="af005">Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></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="af005">Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck</wicri:regionArea><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion><wicri:noRegion>23538 Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af015">German Center for Infection Research (DZIF), Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>German Center for Infection Research (DZIF)</wicri:regionArea></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Highlights</title><p><list list-type="simple" id="l0005"><list-item id="o0005"><label>•</label><p id="p0165">The 3D structure of the MERS-CoV papain-like protease (PL<sup>pro</sup>) has been determined.</p></list-item><list-item id="o0010"><label>•</label><p id="p0170">The enzyme has a deficient oxyanion hole and unique S3 as well as S5 subsites.</p></list-item><list-item id="o0015"><label>•</label><p id="p0175"><italic>In-vitro</italic> kinetics of the MERS-CoV PL<sup>pro</sup> are slower than for the SARS-CoV enzyme.</p></list-item><list-item id="o0020"><label>•</label><p id="p0180">Restoring the oxyanion hole through mutagenesis enhances the enzyme kinetics.</p></list-item><list-item id="o0025"><label>•</label><p id="p0185">The unique features of the enzyme will allow design of MERS-specific antivirals.</p></list-item></list></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Anand, K" uniqKey="Anand K">K. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res</journal-id><journal-title-group><journal-title>Antiviral Research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn><publisher><publisher-name>The Authors. Published by Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24992731</article-id><article-id pub-id-type="pmc">7113875</article-id><article-id pub-id-type="publisher-id">S0166-3542(14)00173-9</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2014.06.011</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features</article-title></title-group><contrib-group><contrib contrib-type="author" id="au005"><name><surname>Lei</surname><given-names>Jian</given-names></name><xref rid="af005" ref-type="aff">a</xref><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au010"><name><surname>Mesters</surname><given-names>Jeroen R.</given-names></name><xref rid="af005" ref-type="aff">a</xref><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au015"><name><surname>Drosten</surname><given-names>Christian</given-names></name><xref rid="af010" ref-type="aff">b</xref><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au020"><name><surname>Anemüller</surname><given-names>Stefan</given-names></name><xref rid="af005" ref-type="aff">a</xref><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au025"><name><surname>Ma</surname><given-names>Qingjun</given-names></name><xref rid="af005" ref-type="aff">a</xref><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au030"><name><surname>Hilgenfeld</surname><given-names>Rolf</given-names></name><email>hilgenfeld@biochem.uni-luebeck.de</email><xref rid="af005" ref-type="aff">a</xref><xref rid="af015" ref-type="aff">c</xref><xref rid="cor1" ref-type="corresp">⁎</xref></contrib></contrib-group><aff id="af005"><label>a</label>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</aff><aff id="af010"><label>b</label>Institute of Virology, University of Bonn Medical School, 53127 Bonn, Germany</aff><aff id="af015"><label>c</label>German Center for Infection Research (DZIF), Germany</aff><author-notes><corresp id="cor1"><label>⁎</label>Corresponding author at: Institute of Biochemistry, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Tel.: +49 451 500 4060; fax: +49 451 500 4068. <email>hilgenfeld@biochem.uni-luebeck.de</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>30</day><month>6</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>9</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>30</day><month>6</month><year>2014</year></pub-date><volume>109</volume><fpage>72</fpage><lpage>82</lpage><history><date date-type="received"><day>8</day><month>5</month><year>2014</year></date><date date-type="rev-recd"><day>14</day><month>6</month><year>2014</year></date><date date-type="accepted"><day>18</day><month>6</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors</copyright-statement><copyright-year>2014</copyright-year><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract abstract-type="author-highlights" id="ab005"><title>Highlights</title><p><list list-type="simple" id="l0005"><list-item id="o0005"><label>•</label><p id="p0165">The 3D structure of the MERS-CoV papain-like protease (PL<sup>pro</sup>) has been determined.</p></list-item><list-item id="o0010"><label>•</label><p id="p0170">The enzyme has a deficient oxyanion hole and unique S3 as well as S5 subsites.</p></list-item><list-item id="o0015"><label>•</label><p id="p0175"><italic>In-vitro</italic> kinetics of the MERS-CoV PL<sup>pro</sup> are slower than for the SARS-CoV enzyme.</p></list-item><list-item id="o0020"><label>•</label><p id="p0180">Restoring the oxyanion hole through mutagenesis enhances the enzyme kinetics.</p></list-item><list-item id="o0025"><label>•</label><p id="p0185">The unique features of the enzyme will allow design of MERS-specific antivirals.</p></list-item></list></p></abstract><abstract id="ab010"><p>The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL<sup>pro</sup>) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL<sup>pro</sup> is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced <italic>in vitro</italic> peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL<sup>pro</sup>, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the <italic>in vitro</italic> catalytic activity of the MERS-CoV PL<sup>pro</sup>. The unique features observed in the crystal structure of the MERS-CoV PL<sup>pro</sup> should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.</p></abstract><kwd-group id="kg005"><title>Keywords</title><kwd>MERS-CoV</kwd><kwd>Papain-like protease</kwd><kwd>Oxyanion hole</kwd><kwd>Zinc finger</kwd><kwd>Deubiquitinase</kwd><kwd>Antiviral drug design</kwd></kwd-group></article-meta></front></pmc><affiliations><list><country><li>Allemagne</li></country><region><li>District de Cologne</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Lei, Jian" sort="Lei, Jian" uniqKey="Lei J" first="Jian" last="Lei">Jian Lei</name></noRegion><name sortKey="Anemuller, Stefan" sort="Anemuller, Stefan" uniqKey="Anemuller S" first="Stefan" last="Anemüller">Stefan Anemüller</name><name sortKey="Anemuller, Stefan" sort="Anemuller, Stefan" uniqKey="Anemuller S" first="Stefan" last="Anemüller">Stefan Anemüller</name><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><name sortKey="Lei, Jian" sort="Lei, Jian" uniqKey="Lei J" first="Jian" last="Lei">Jian Lei</name><name sortKey="Ma, Qingjun" sort="Ma, Qingjun" uniqKey="Ma Q" first="Qingjun" last="Ma">Qingjun Ma</name><name sortKey="Ma, Qingjun" sort="Ma, Qingjun" uniqKey="Ma Q" first="Qingjun" last="Ma">Qingjun Ma</name><name sortKey="Mesters, Jeroen R" sort="Mesters, Jeroen R" uniqKey="Mesters J" first="Jeroen R." last="Mesters">Jeroen R. Mesters</name><name sortKey="Mesters, Jeroen R" sort="Mesters, Jeroen R" uniqKey="Mesters J" first="Jeroen R." last="Mesters">Jeroen R. Mesters</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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