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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structures of the <italic>Middle East respiratory syndrome coronavirus</italic> 3C‐like protease reveal insights into substrate specificity</title><author><name sortKey="Needle, Danielle" sort="Needle, Danielle" uniqKey="Needle D" first="Danielle" last="Needle">Danielle Needle</name></author><author><name sortKey="Lountos, George T" sort="Lountos, George T" uniqKey="Lountos G" first="George T." last="Lountos">George T. Lountos</name></author><author><name sortKey="Waugh, David S" sort="Waugh, David S" uniqKey="Waugh D" first="David S." last="Waugh">David S. Waugh</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25945576</idno><idno type="pmc">4427198</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427198</idno><idno type="RBID">PMC:4427198</idno><idno type="doi">10.1107/S1399004715003521</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000976</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000976</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structures of the <italic>Middle East respiratory syndrome coronavirus</italic> 3C‐like protease reveal insights into substrate specificity</title><author><name sortKey="Needle, Danielle" sort="Needle, Danielle" uniqKey="Needle D" first="Danielle" last="Needle">Danielle Needle</name></author><author><name sortKey="Lountos, George T" sort="Lountos, George T" uniqKey="Lountos G" first="George T." last="Lountos">George T. Lountos</name></author><author><name sortKey="Waugh, David S" sort="Waugh, David S" uniqKey="Waugh D" first="David S." last="Waugh">David S. Waugh</name></author></analytic><series><title level="j">Acta Crystallographica Section D: Biological Crystallography</title><idno type="ISSN">0907-4449</idno><idno type="eISSN">1399-0047</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><italic>Middle East respiratory syndrome coronavirus</italic> (MERS‐CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi‐organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive‐stranded RNA MERS‐CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain‐like protease and at 11 sites by a 3C‐like protease (3CL<sup>pro</sup>). Since 3CL<sup>pro</sup> is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CL<sup>pro</sup> inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS‐CoV 3CL<sup>pro</sup> enzyme were determined. The aim was to co‐crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C‐terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme–product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS‐CoV 3CL<sup>pro</sup>; however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure‐based design of small‐molecule inhibitors of the MERS‐CoV 3CL<sup>pro</sup> enzyme.</p></div></front></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Acta Crystallogr D Biol Crystallogr</journal-id><journal-id journal-id-type="iso-abbrev">Acta Crystallogr. D Biol. Crystallogr</journal-id><journal-id journal-id-type="doi">10.1107/S13990047</journal-id><journal-id journal-id-type="publisher-id">AYD2</journal-id><journal-title-group><journal-title>Acta Crystallographica Section D: Biological Crystallography</journal-title></journal-title-group><issn pub-type="ppub">0907-4449</issn><issn pub-type="epub">1399-0047</issn><publisher><publisher-name>International Union of Crystallography</publisher-name><publisher-loc>5 Abbey Square, Chester, Cheshire CH1 2HU, England</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25945576</article-id><article-id pub-id-type="pmc">4427198</article-id><article-id pub-id-type="doi">10.1107/S1399004715003521</article-id><article-id pub-id-type="publisher-id">AYD2RR5092</article-id><article-id pub-id-type="other">rr5092</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Papers</subject></subj-group></article-categories><title-group><article-title>Structures of the <italic>Middle East respiratory syndrome coronavirus</italic> 3C‐like protease reveal insights into substrate specificity</article-title><alt-title alt-title-type="right-running-head">MERS‐CoV 3C‐like protease</alt-title></title-group><contrib-group><contrib id="cr1" contrib-type="author"><name><surname>Needle</surname><given-names>Danielle</given-names></name></contrib><contrib id="cr2" contrib-type="author"><name><surname>Lountos</surname><given-names>George T.</given-names></name></contrib><contrib id="cr3" contrib-type="author"><name><surname>Waugh</surname><given-names>David S.</given-names></name></contrib></contrib-group><aff id="a1"><label><sup>1</sup></label>Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA</aff><aff id="a2"><label><sup>2</sup></label>Basic Science Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA</aff><author-notes><corresp id="correspondenceTo">David S. Waugh, e‐mail: <email>waughd@mail.nih.gov</email></corresp></author-notes><pub-date pub-type="epub"><day>11</day><month>5</month><year>2015</year></pub-date><pub-date pub-type="ppub"><month>5</month><year>2015</year></pub-date><volume>71</volume><issue>5</issue><issue-id pub-id-type="doi">10.1111/ayd2.2015.71.issue-5</issue-id><fpage>1102</fpage><lpage>1111</lpage><history><pmc-comment>supplied string: Received 20 November 2014, accepted 19 February 2015</pmc-comment>
<date date-type="received"><day>20</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>19</day><month>2</month><year>2015</year></date></history><permissions><copyright-statement content-type="article-copyright">International Union of Crystallography, 2015</copyright-statement><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="file:AYD2-71-1102.pdf"></self-uri><abstract><p><italic>Middle East respiratory syndrome coronavirus</italic> (MERS‐CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi‐organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive‐stranded RNA MERS‐CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain‐like protease and at 11 sites by a 3C‐like protease (3CL<sup>pro</sup>). Since 3CL<sup>pro</sup> is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CL<sup>pro</sup> inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS‐CoV 3CL<sup>pro</sup> enzyme were determined. The aim was to co‐crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C‐terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme–product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS‐CoV 3CL<sup>pro</sup>; however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure‐based design of small‐molecule inhibitors of the MERS‐CoV 3CL<sup>pro</sup> enzyme.</p></abstract><kwd-group><kwd id="k1">MERS‐CoV</kwd><kwd id="k2">coronavirus</kwd><kwd id="k3">main protease</kwd><kwd id="k4">3CL<sup>pro</sup></kwd></kwd-group><counts><count count-type="links-crossref" count="0"></count><count count-type="links-pubmed" count="0"></count><fig-count count="0"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="0"></ref-count><word-count count="0"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>May 2015</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020</meta-value></custom-meta></custom-meta-group></article-meta></front><body><p>The full text for this article, hosted at <ext-link ext-link-type="uri" xlink:href="http://journals.iucr.org">http://journals.iucr.org</ext-link>, is unavailable due to technical difficulties.</p><sec sec-type="supplementary-material"><title>Supporting information</title><supplementary-material content-type="local-data"><p>PDB reference: <ext-link ext-link-type="uri" xlink:href="http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wmd">http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wmd</ext-link></p><p>PDB reference: <ext-link ext-link-type="uri" xlink:href="http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wme">http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wme</ext-link></p><p>PDB reference: <ext-link ext-link-type="uri" xlink:href="http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wmf">http://scripts.iucr.org/cgi-bin/cr.cgi?rm=pdb&pdbId=4wmf</ext-link></p></supplementary-material></sec></body></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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