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Structural and functional definition of a vulnerable site on the hemagglutinin of highly pathogenic avian influenza A virus H5N1

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  • Structural and functional definition of a vulnerable site on the hemagglutinin of highly pathogenic avian influenza A virus H5N1

    J Biol Chem. 2019 Feb 8. pii: jbc.RA118.007008. doi: 10.1074/jbc.RA118.007008. [Epub ahead of print]
    Structural and functional definition of a vulnerable site on the hemagglutinin of highly pathogenic avian influenza A virus H5N1.

    Wang P1, Zuo Y1, Sun J1, Zuo T1, Zhang S1, Guo S1, Shi X1, Liang M2, Zhou P3, Zhang L4, Wang X1.
    Author information

    Abstract

    Most neutralizing antibodies against highly pathogenic avian influenza A virus H5N1 recognize the receptor-binding site (RBS) on the globular head domain and the stem of H5N1 hemagglutinin (HA). Through comprehensive analysis of multiple human protective antibodies, we previously identified four vulnerable sites (VS1-VS4) on the globular head domain. Among them, the VS1, occupying the opposite side of the RBS on the same HA, was defined by the epitope of antibody 65C6. In this study, we report the crystal structures of two additional human H5N1 antibodies isolated from H5N1-infected individuals, 3C11 and AVFluIgG01, bound to the head at 2.33 and 2.30 resolution, respectively. These two new antibody epitopes have large overlap with and extend beyond the original VS1. Site-directed mutagenesis experiments identified eight pivotal residues (Ser-126b, Lys-165, Arg-166, Ser-167, Tyr-168, Asn-169, Thr-171, and Asn-172) critical for 65C6, 3C11 and AVFluIgG01 binding and neutralization activities. These residues formed a unique "Y"-shape surface on H5N1 globular head and are highly conserved among H5N1 viruses. Our results further support the existence of a vulnerable site distinct from the RBS and the stem region of H5N1 HA, and future design of immunogens should take this particular site into consideration.
    Published under license by The American Society for Biochemistry and Molecular Biology, Inc.


    KEYWORDS:

    H5N1; HPAI; X-ray crystallography; epitope; infectious disease; influenza; influenza virus; monoclonal antibody; mutagenesis; neutralizing antibody; structural biology; vaccine development; virology; vulnerable site

    PMID: 30737282 DOI: 10.1074/jbc.RA118.007008
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