X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design
Identifieur interne : 000671 ( Pmc/Checkpoint ); précédent : 000670; suivant : 000672X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design
Auteurs : Jozlyn R. Clasman [États-Unis] ; Yahira M. Báez-Santos [États-Unis] ; Robert C. Mettelman [États-Unis] ; Amornrat O Rien [États-Unis] ; Susan C. Baker [États-Unis] ; Andrew D. Mesecar [États-Unis]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro
The online version of this article (doi:10.1038/srep40292) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1038/srep40292
PubMed: 28079137
PubMed Central: 5228125
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Clasman</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.169077.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1937 2197</institution-id><institution>Department of Biological Sciences,</institution><institution>Purdue University,</institution></institution-wrap>West Lafayette, IN USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Baez Santos, Yahira M" sort="Baez Santos, Yahira M" uniqKey="Baez Santos Y" first="Yahira M." last="Báez-Santos">Yahira M. 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Baker</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.164971.c</institution-id><institution-id institution-id-type="ISNI">0000 0001 1089 6558</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>Loyola University Chicago, Stritch School of Medicine,</institution></institution-wrap>Maywood, IL USA</nlm:aff><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Maywood</wicri:cityArea></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. 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However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro <italic>in vitro</italic>. The X-ray structure of MERS PLpro-∆Ubl2 was determined to 1.9 Å and compared to PLpro containing the N-terminal Ubl2 domain. While the structures were nearly identical, the PLpro-∆Ubl2 enzyme revealed the intact structure of the substrate-binding loop. Moreover, PLpro-∆Ubl2 catalysis against different substrates and a purported inhibitor revealed no differences in catalytic efficiency, substrate specificity, and inhibition. Further, no changes in thermal stability were observed between enzymes. We conclude that the catalytic core of MERS PLpro, i.e. without the Ubl2 domain, is sufficient for catalysis and stability <italic>in vitro</italic> with utility to evaluate potential inhibitors as a platform for structure-based drug design.</p><sec><title>Supplementary information</title><p>The online version of this article (doi:10.1038/srep40292) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barretto, N" uniqKey="Barretto N">N 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uniqKey="Fujii S">S Fujii</name></author><author><name sortKey="Kato, K" uniqKey="Kato K">K Kato</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H" uniqKey="Lee H">H Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baell, J" uniqKey="Baell J">J Baell</name></author><author><name sortKey="Walters, Ma" uniqKey="Walters M">MA Walters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Otwinowski, Z" uniqKey="Otwinowski Z">Z Otwinowski</name></author><author><name sortKey="Minor, W" uniqKey="Minor W">W Minor</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="Afonine, Pv" uniqKey="Afonine P">PV 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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">28079137</article-id><article-id pub-id-type="pmc">5228125</article-id><article-id pub-id-type="publisher-id">BFsrep40292</article-id><article-id pub-id-type="doi">10.1038/srep40292</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Clasman</surname><given-names>Jozlyn R.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Báez-Santos</surname><given-names>Yahira M.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Mettelman</surname><given-names>Robert C.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>O’Brien</surname><given-names>Amornrat</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Baker</surname><given-names>Susan C.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Mesecar</surname><given-names>Andrew D.</given-names></name><address><email>amesecar@purdue.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.169077.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1937 2197</institution-id><institution>Department of Biological Sciences,</institution><institution>Purdue University,</institution></institution-wrap>West Lafayette, IN USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.164971.c</institution-id><institution-id institution-id-type="ISNI">0000 0001 1089 6558</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>Loyola University Chicago, Stritch School of Medicine,</institution></institution-wrap>Maywood, IL USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.169077.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1937 2197</institution-id><institution>Department of Biochemistry,</institution><institution>Purdue University,</institution></institution-wrap>West Lafayette, IN USA</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.169077.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1937 2197</institution-id><institution>Center for Cancer Research, Purdue University,</institution></institution-wrap>West Lafayette, IN USA</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.169077.e</institution-id><institution-id institution-id-type="ISNI">0000 0004 1937 2197</institution-id><institution>Present Address: Present address: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.,</institution></institution-wrap>,</aff></contrib-group><pub-date pub-type="epub"><day>12</day><month>1</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>1</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>40292</elocation-id><history><date date-type="received"><day>31</day><month>8</month><year>2016</year></date><date date-type="accepted"><day>5</day><month>12</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s) 2017</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 id="Par1">Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro <italic>in vitro</italic>. The X-ray structure of MERS PLpro-∆Ubl2 was determined to 1.9 Å and compared to PLpro containing the N-terminal Ubl2 domain. While the structures were nearly identical, the PLpro-∆Ubl2 enzyme revealed the intact structure of the substrate-binding loop. Moreover, PLpro-∆Ubl2 catalysis against different substrates and a purported inhibitor revealed no differences in catalytic efficiency, substrate specificity, and inhibition. Further, no changes in thermal stability were observed between enzymes. We conclude that the catalytic core of MERS PLpro, i.e. without the Ubl2 domain, is sufficient for catalysis and stability <italic>in vitro</italic> with utility to evaluate potential inhibitors as a platform for structure-based drug design.</p><sec><title>Supplementary information</title><p>The online version of this article (doi:10.1038/srep40292) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Enzyme mechanisms</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) 2017</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li><li>Indiana</li></region></list><tree><country name="États-Unis"><region name="Indiana"><name sortKey="Clasman, Jozlyn R" sort="Clasman, Jozlyn R" uniqKey="Clasman J" first="Jozlyn R." last="Clasman">Jozlyn R. Clasman</name></region><name sortKey="Baez Santos, Yahira M" sort="Baez Santos, Yahira M" uniqKey="Baez Santos Y" first="Yahira M." last="Báez-Santos">Yahira M. Báez-Santos</name><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name><name sortKey="Mettelman, Robert C" sort="Mettelman, Robert C" uniqKey="Mettelman R" first="Robert C." last="Mettelman">Robert C. Mettelman</name><name sortKey="O Rien, Amornrat" sort="O Rien, Amornrat" uniqKey="O Rien A" first="Amornrat" last="O Rien">Amornrat O Rien</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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