Conformational Polymorphism of m7GTP in Crystal Structure of the PB2 Middle Domain from Human Influenza A Virus
Identifieur interne : 000B73 ( Pmc/Curation ); précédent : 000B72; suivant : 000B74Conformational Polymorphism of m7GTP in Crystal Structure of the PB2 Middle Domain from Human Influenza A Virus
Auteurs : Toshiharu Tsurumura [Japon] ; Hao Qiu [Japon] ; Toru Yoshida [Japon] ; Yayoi Tsumori [Japon] ; Dai Hatakeyama [Japon] ; Takashi Kuzuhara [Japon] ; Hideaki Tsuge [Japon]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
Influenza pandemics with human-to-human transmission of the virus are of great public concern. It is now recognized that a number of factors are necessary for human transmission and virulence, including several key mutations within the PB2 subunit of RNA-dependent RNA polymerase. The structure of the middle domain in PB2 has been revealed with or without m7GTP, thus the middle domain is considered to be novel target for structure-based drug design. Here we report the crystal structure of the middle domain of H1N1 PB2 with or without m7GTP at 1.9Å and 2.0Å resolution, respectively, which has two mutations (P453H, I471T) to increase electrostatic potential and solubility. Here we report the m7GTP has unique conformation differ from the reported structure. 7-methyl-guanine is fixed in the pocket, but particularly significant change is seen in ribose and triphosphate region: the buried 7-methyl-guanine indeed binds in the pocket forming by H357, F404, E361 and K376 but the triphosphate continues directly to the outer domain. The presented conformation of m7GTP may be a clue for the anti-influenza drug-design.
Url:
DOI: 10.1371/journal.pone.0082020
PubMed: 24312396
PubMed Central: 3843726
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<front><div type="abstract" xml:lang="en"><p>Influenza pandemics with human-to-human transmission of the virus are of great public concern. It is now recognized that a number of factors are necessary for human transmission and virulence, including several key mutations within the PB2 subunit of RNA-dependent RNA polymerase. The structure of the middle domain in PB2 has been revealed with or without m<sup>7</sup>
GTP, thus the middle domain is considered to be novel target for structure-based drug design. Here we report the crystal structure of the middle domain of H1N1 PB2 with or without m<sup>7</sup>
GTP at 1.9Å and 2.0Å resolution, respectively, which has two mutations (P453H, I471T) to increase electrostatic potential and solubility. Here we report the m<sup>7</sup>
GTP has unique conformation differ from the reported structure. 7-methyl-guanine is fixed in the pocket, but particularly significant change is seen in ribose and triphosphate region: the buried 7-methyl-guanine indeed binds in the pocket forming by H357, F404, E361 and K376 but the triphosphate continues directly to the outer domain. The presented conformation of m<sup>7</sup>
GTP may be a clue for the anti-influenza drug-design.</p>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24312396</article-id>
<article-id pub-id-type="pmc">3843726</article-id>
<article-id pub-id-type="publisher-id">PONE-D-13-36305</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0082020</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Conformational Polymorphism of m<sup>7</sup>
GTP in Crystal Structure of the PB2 Middle Domain from Human Influenza A Virus</article-title>
<alt-title alt-title-type="running-head">Conformational Polymorphism of m<sup>7</sup>
GTP in PB2</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Tsurumura</surname>
<given-names>Toshiharu</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Qiu</surname>
<given-names>Hao</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yoshida</surname>
<given-names>Toru</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsumori</surname>
<given-names>Yayoi</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hatakeyama</surname>
<given-names>Dai</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kuzuhara</surname>
<given-names>Takashi</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsuge</surname>
<given-names>Hideaki</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-Motoyama, Kyoto, Japan</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>de la Torre</surname>
<given-names>Juan C.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>The Scripps Research Institute, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>tsuge@cc.kyoto-su.ac.jp</email>
</corresp>
<fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: TT HT. Performed the experiments: TT HQ YT HT. Analyzed the data: TT TY HT. Wrote the manuscript: TT HT. Discussion of the manuscript: TT TY DH TK HT. </p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>29</day>
<month>11</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<issue>11</issue>
<elocation-id>e82020</elocation-id>
<history><date date-type="received"><day>4</day>
<month>9</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>28</day>
<month>10</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© 2013 Tsurumura et al</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>Tsurumura et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>Influenza pandemics with human-to-human transmission of the virus are of great public concern. It is now recognized that a number of factors are necessary for human transmission and virulence, including several key mutations within the PB2 subunit of RNA-dependent RNA polymerase. The structure of the middle domain in PB2 has been revealed with or without m<sup>7</sup>
GTP, thus the middle domain is considered to be novel target for structure-based drug design. Here we report the crystal structure of the middle domain of H1N1 PB2 with or without m<sup>7</sup>
GTP at 1.9Å and 2.0Å resolution, respectively, which has two mutations (P453H, I471T) to increase electrostatic potential and solubility. Here we report the m<sup>7</sup>
GTP has unique conformation differ from the reported structure. 7-methyl-guanine is fixed in the pocket, but particularly significant change is seen in ribose and triphosphate region: the buried 7-methyl-guanine indeed binds in the pocket forming by H357, F404, E361 and K376 but the triphosphate continues directly to the outer domain. The presented conformation of m<sup>7</sup>
GTP may be a clue for the anti-influenza drug-design.</p>
</abstract>
<funding-group><funding-statement>This work supported in part by a Strategic Research Foundation Grant-aided Project for Private Universities and Grant-in-Aid for Scientific Research on Innovative Areas, MEXT/JSPS KAKENHI grant number 25121733 of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
</article-meta>
</front>
</pmc>
</record>
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