Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism
Identifieur interne : 000712 ( Pmc/Checkpoint ); précédent : 000711; suivant : 000713Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism
Auteurs : Maria Batool ; Masaud Shah ; Mahesh Chandra Patra ; Dhanusha Yesudhas ; Sangdun ChoiSource :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host’s immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system. Multiple variants of p4a-dsRNA were created and investigated through extensive molecular dynamics procedures to highlight crucial interfacial residues that may be used as potential pharmacophores for future drug development. The structural analysis revealed that p4a exhibits a typical αβββα fold structure, as found in other dsRNA-binding proteins. The α1 helix and the β1-β2 loop play a crucial role in recognizing and establishing contacts with the minor grooves of dsRNA. Further, mutational and binding free energy analyses suggested that in addition to K63 and K67, two other residues, K27 and W45, might also be crucial for p4a-dsRNA stability.
Url:
DOI: 10.1038/s41598-017-11736-6
PubMed: 28900197
PubMed Central: 5596018
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism</title><author><name sortKey="Batool, Maria" sort="Batool, Maria" uniqKey="Batool M" first="Maria" last="Batool">Maria Batool</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Shah, Masaud" sort="Shah, Masaud" uniqKey="Shah M" first="Masaud" last="Shah">Masaud Shah</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Patra, Mahesh Chandra" sort="Patra, Mahesh Chandra" uniqKey="Patra M" first="Mahesh Chandra" last="Patra">Mahesh Chandra Patra</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Yesudhas, Dhanusha" sort="Yesudhas, Dhanusha" uniqKey="Yesudhas D" first="Dhanusha" last="Yesudhas">Dhanusha Yesudhas</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28900197</idno><idno type="pmc">5596018</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596018</idno><idno type="RBID">PMC:5596018</idno><idno type="doi">10.1038/s41598-017-11736-6</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000447</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000447</idno><idno type="wicri:Area/Pmc/Curation">000447</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000447</idno><idno type="wicri:Area/Pmc/Checkpoint">000712</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000712</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism</title><author><name sortKey="Batool, Maria" sort="Batool, Maria" uniqKey="Batool M" first="Maria" last="Batool">Maria Batool</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Shah, Masaud" sort="Shah, Masaud" uniqKey="Shah M" first="Masaud" last="Shah">Masaud Shah</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Patra, Mahesh Chandra" sort="Patra, Mahesh Chandra" uniqKey="Patra M" first="Mahesh Chandra" last="Patra">Mahesh Chandra Patra</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Yesudhas, Dhanusha" sort="Yesudhas, Dhanusha" uniqKey="Yesudhas D" first="Dhanusha" last="Yesudhas">Dhanusha Yesudhas</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host’s immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system. Multiple variants of p4a-dsRNA were created and investigated through extensive molecular dynamics procedures to highlight crucial interfacial residues that may be used as potential pharmacophores for future drug development. The structural analysis revealed that p4a exhibits a typical αβββα fold structure, as found in other dsRNA-binding proteins. The α1 helix and the β1-β2 loop play a crucial role in recognizing and establishing contacts with the minor grooves of dsRNA. 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Gohlke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miller, Br" uniqKey="Miller B">BR Miller</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<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">28900197</article-id><article-id pub-id-type="pmc">5596018</article-id><article-id pub-id-type="publisher-id">11736</article-id><article-id pub-id-type="doi">10.1038/s41598-017-11736-6</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Batool</surname><given-names>Maria</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Masaud</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Patra</surname><given-names>Mahesh Chandra</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Yesudhas</surname><given-names>Dhanusha</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Choi</surname><given-names>Sangdun</given-names></name><address><email>sangdunchoi@ajou.ac.kr</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0532 3933</institution-id><institution-id institution-id-type="GRID">grid.251916.8</institution-id><institution>Department of Molecular Science and Technology, Ajou University,</institution></institution-wrap>Suwon, 16499 South Korea</aff></contrib-group><pub-date pub-type="epub"><day>12</day><month>9</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>9</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>11362</elocation-id><history><date date-type="received"><day>23</day><month>1</month><year>2017</year></date><date date-type="accepted"><day>29</day><month>8</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s) 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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">Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host’s immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system. Multiple variants of p4a-dsRNA were created and investigated through extensive molecular dynamics procedures to highlight crucial interfacial residues that may be used as potential pharmacophores for future drug development. The structural analysis revealed that p4a exhibits a typical αβββα fold structure, as found in other dsRNA-binding proteins. The α1 helix and the β1-β2 loop play a crucial role in recognizing and establishing contacts with the minor grooves of dsRNA. Further, mutational and binding free energy analyses suggested that in addition to K63 and K67, two other residues, K27 and W45, might also be crucial for p4a-dsRNA stability.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Cellular signalling networks</kwd><kwd>Computational models</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></list><tree><noCountry><name sortKey="Batool, Maria" sort="Batool, Maria" uniqKey="Batool M" first="Maria" last="Batool">Maria Batool</name><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name><name sortKey="Patra, Mahesh Chandra" sort="Patra, Mahesh Chandra" uniqKey="Patra M" first="Mahesh Chandra" last="Patra">Mahesh Chandra Patra</name><name sortKey="Shah, Masaud" sort="Shah, Masaud" uniqKey="Shah M" first="Masaud" last="Shah">Masaud Shah</name><name sortKey="Yesudhas, Dhanusha" sort="Yesudhas, Dhanusha" uniqKey="Yesudhas D" first="Dhanusha" last="Yesudhas">Dhanusha Yesudhas</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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