Mechanism of 150-cavity formation in influenza neuraminidase
Identifieur interne : 000C36 ( Main/Exploration ); précédent : 000C35; suivant : 000C37Mechanism of 150-cavity formation in influenza neuraminidase
Auteurs : Rommie E. Amaro [États-Unis] ; Robert V. Swift [États-Unis] ; Lane Votapka [États-Unis] ; Wilfred W. Li [États-Unis] ; Ross C. Walker [États-Unis] ; Robin M. Bush [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2011.
Abstract
The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 μs of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.
Url:
DOI: 10.1038/ncomms1390
PubMed: 21750542
PubMed Central: 3144582
Affiliations:
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Amaro</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California</institution>, Irvine, California 92697<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Swift, Robert V" sort="Swift, Robert V" uniqKey="Swift R" first="Robert V." last="Swift">Robert V. Swift</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California</institution>, Irvine, California 92697<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Votapka, Lane" sort="Votapka, Lane" uniqKey="Votapka L" first="Lane" last="Votapka">Lane Votapka</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California</institution>, Irvine, California 92697<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Li, Wilfred W" sort="Li, Wilfred W" uniqKey="Li W" first="Wilfred W." last="Li">Wilfred W. Li</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Biomedical Computation Resource, University of California</institution>,<institution>San Diego</institution>, La Jolla, California 92093<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Walker, Ross C" sort="Walker, Ross C" uniqKey="Walker R" first="Ross C." last="Walker">Ross C. Walker</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Chemistry and Biochemistry, San Diego Supercomputer Center, University of California</institution>,<institution>San Diego</institution>, La Jolla California 92093<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bush, Robin M" sort="Bush, Robin M" uniqKey="Bush R" first="Robin M." last="Bush">Robin M. Bush</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Ecology and Evolutionary Biology, University of California</institution>, Irvine, California 92697<country>USA</country>.</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 μs of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Russell, R J" uniqKey="Russell R">R. J. 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