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Article: Structural basis and sequence co-evolution analysis of the hemagglutinin protein of pandemic influenza A/H1N1 (2009) virus
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TitleStructural basis and sequence co-evolution analysis of the hemagglutinin protein of pandemic influenza A/H1N1 (2009) virus
 
AuthorsTse, H1
Kao, RYT1
Wu, WL1
Lim, WWL2
Chen, H1
Yeung, MY1
Woo, PCY1
Sze, KH1
Yuen, KY1
 
KeywordsCo-evolution
D222g
Hemagglutinin
Influenza a
Pandemic
Structural evolution
 
Issue Date2011
 
PublisherSociety for Experimental Biology and Medicine. The Journal's web site is located at http://www.ebmonline.org/
 
CitationExperimental Biology And Medicine, 2011, v. 236 n. 8, p. 915-925 [How to Cite?]
DOI: http://dx.doi.org/10.1258/ebm.2011.010264
 
AbstractSevere pandemic influenza A H1N1 (2009) infection, especially in the lower respiratory tract, is often associated with the virus carrying a D222G substitution in the hemagglutinin (HA) protein of the virus. The mechanism for this association has not been fully explored. In the in vitro binding assay, it was found that clinical isolates carrying D222G substitution exhibit higher binding avidity to 2,3-linked sialic acids than the wild-type virus. The receptor binding pocket of the pandemic influenza (H1N1) HA was found to be smaller than those of other influenza A strains, allowing tighter binding of the virus with the receptor, yet also inducing steric stress for the binding. Our homology modeling and molecular docking calculations implicated that residue 222 may affect the positioning of the conserved Q223 residue, hence modulating flexibility of the binding pocket and steric hindrance during receptor binding. The molecular property of residue 222 can also directly influence the 'lysine fence' via the polarity of the amino acid residue where D222G substitution will enhance the electrostatic interactions between the receptor and the protein. The potential importance of residue 222 was illustrated by evolutionary analysis, which showed that this site is under intense selection pressure during adaptation of the virus to human host. Our findings provide a useful reference for follow-up studies in monitoring the ongoing evolution of the pandemic influenza A H1N1 (2009) virus. © 2011 by the Society for Experimental Biology and Medicine.
 
ISSN1535-3702
2013 Impact Factor: 2.226
2013 SCImago Journal Rankings: 1.150
 
DOIhttp://dx.doi.org/10.1258/ebm.2011.010264
 
ISI Accession Number IDWOS:000293877200004
Funding AgencyGrant Number
Ted Sun Foundation
Providence Foundation Limited
Hong Kong Special Administrative Region Research Grant Council
Food and Health Bureau of the Hong Kong Special Administrative Region
Shaw Foundation
Funding Information:

This work is partly supported by the Ted Sun Foundation, Providence Foundation Limited in memory of the late Dr Lui Hac Minh, the Hong Kong Special Administrative Region Research Grant Council, Research Fund for the Control of Infectious Diseases of the Food and Health Bureau of the Hong Kong Special Administrative Region, and The Shaw Foundation. We thank Dr Kelvin To for reading the manuscript.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorTse, H
 
dc.contributor.authorKao, RYT
 
dc.contributor.authorWu, WL
 
dc.contributor.authorLim, WWL
 
dc.contributor.authorChen, H
 
dc.contributor.authorYeung, MY
 
dc.contributor.authorWoo, PCY
 
dc.contributor.authorSze, KH
 
dc.contributor.authorYuen, KY
 
dc.date.accessioned2011-10-28T02:43:13Z
 
dc.date.available2011-10-28T02:43:13Z
 
dc.date.issued2011
 
dc.description.abstractSevere pandemic influenza A H1N1 (2009) infection, especially in the lower respiratory tract, is often associated with the virus carrying a D222G substitution in the hemagglutinin (HA) protein of the virus. The mechanism for this association has not been fully explored. In the in vitro binding assay, it was found that clinical isolates carrying D222G substitution exhibit higher binding avidity to 2,3-linked sialic acids than the wild-type virus. The receptor binding pocket of the pandemic influenza (H1N1) HA was found to be smaller than those of other influenza A strains, allowing tighter binding of the virus with the receptor, yet also inducing steric stress for the binding. Our homology modeling and molecular docking calculations implicated that residue 222 may affect the positioning of the conserved Q223 residue, hence modulating flexibility of the binding pocket and steric hindrance during receptor binding. The molecular property of residue 222 can also directly influence the 'lysine fence' via the polarity of the amino acid residue where D222G substitution will enhance the electrostatic interactions between the receptor and the protein. The potential importance of residue 222 was illustrated by evolutionary analysis, which showed that this site is under intense selection pressure during adaptation of the virus to human host. Our findings provide a useful reference for follow-up studies in monitoring the ongoing evolution of the pandemic influenza A H1N1 (2009) virus. © 2011 by the Society for Experimental Biology and Medicine.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationExperimental Biology And Medicine, 2011, v. 236 n. 8, p. 915-925 [How to Cite?]
DOI: http://dx.doi.org/10.1258/ebm.2011.010264
 
dc.identifier.doihttp://dx.doi.org/10.1258/ebm.2011.010264
 
dc.identifier.eissn1535-3699
 
dc.identifier.epage925
 
dc.identifier.hkuros197184
 
dc.identifier.isiWOS:000293877200004
Funding AgencyGrant Number
Ted Sun Foundation
Providence Foundation Limited
Hong Kong Special Administrative Region Research Grant Council
Food and Health Bureau of the Hong Kong Special Administrative Region
Shaw Foundation
Funding Information:

This work is partly supported by the Ted Sun Foundation, Providence Foundation Limited in memory of the late Dr Lui Hac Minh, the Hong Kong Special Administrative Region Research Grant Council, Research Fund for the Control of Infectious Diseases of the Food and Health Bureau of the Hong Kong Special Administrative Region, and The Shaw Foundation. We thank Dr Kelvin To for reading the manuscript.

 
dc.identifier.issn1535-3702
2013 Impact Factor: 2.226
2013 SCImago Journal Rankings: 1.150
 
dc.identifier.issue8
 
dc.identifier.pmid21727184
 
dc.identifier.scopuseid_2-s2.0-79961186167
 
dc.identifier.spage915
 
dc.identifier.urihttp://hdl.handle.net/10722/142329
 
dc.identifier.volume236
 
dc.languageeng
 
dc.publisherSociety for Experimental Biology and Medicine. The Journal's web site is located at http://www.ebmonline.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofExperimental Biology and Medicine
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshBinding Sites
 
dc.subject.meshDisease Outbreaks
 
dc.subject.meshEvolution, Molecular
 
dc.subject.meshHemagglutinin Glycoproteins, Influenza Virus - chemistry - genetics
 
dc.subject.meshInfluenza A Virus, H1N1 Subtype - genetics - immunology
 
dc.subjectCo-evolution
 
dc.subjectD222g
 
dc.subjectHemagglutinin
 
dc.subjectInfluenza a
 
dc.subjectPandemic
 
dc.subjectStructural evolution
 
dc.titleStructural basis and sequence co-evolution analysis of the hemagglutinin protein of pandemic influenza A/H1N1 (2009) virus
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Centre for Health Protection