4py8
Crystal structure of Fab 3.1 in complex with the 1918 influenza virus hemagglutinin
Structural highlights
FunctionHEMA_I18A0 Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization of about two third of the virus particles through clathrin-dependent endocytosis and about one third through a clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore (By similarity). Publication Abstract from PubMedA human monoclonal heterosubtypic antibody, mAb 3.1, with its heavy chain encoded by VH3-30, was isolated using phage display with immobilized hemagglutinin from A/Japan/305/1957(H2N2) as the target. Antibody 3.1 potently neutralizes influenza viruses from the H1a clade (i.e. H1, H2, H5, H6), but has little neutralizing activity against the H1b clade. Its crystal structure in complex with HA from a pandemic H1N1 influenza virus A/South Carolina/1/18(H1N1) revealed that, like other heterosubtypic anti-influenza antibodies, mAb3.1 contacts a hydrophobic groove in the HA stem, primarily using its heavy chain. However, in contrast to the closely related mAb FI6 that relies heavily on HCDR3 for binding, mAb 3.1 utilizes residues from HCDR1, HCDR3 and FR3. Interestingly, HCDR1 of mAb 3.1 adopts analpha-helical conformation and engages in very similar hydrophobic interactions with the HA as the de novo in silico designed and affinity matured synthetic protein HB36.3. These findings improved our understanding of the molecular requirements for binding to the conserved epitope in the stem of the HA protein and, therefore, aid the development of more universal influenza vaccines targeting these epitopes. IMPORTANCE: Influenza viruses rapidly evade pre-existing immunity by constantly altering the immunodominant neutralizing antibody epitopes (antigenic drift), or by acquiring new envelope serotypes (antigenic shift). As a consequence, the majority of antibodies elicited by immunization or infection only protect against the immunizing or closely related strains. Here, we describe a novel monoclonal antibody recognizing the conserved heterosubtypic epitope in the stem of influenza A virus hemagglutinin. This antibody, referred to as mAb 3.1, recognizes its epitope in a manner that resembles recognition of a similar epitope by the de novo in silico designed and affinity matured synthetic protein HB36.3. Thus, besides providing novel insights into the molecular interactions between heterosubtypic antibodies and influenza virus hemagglutinin, mAb 3.1 demonstrates that de novo in silico designed and affinity matured synthetic proteins can foretell naturally selected antibody binding. This knowledge will aid development of a pan-influenza vaccine. Alternative Recognition of the Conserved Stem-Epitope in Influenza A Hemagglutinin by a VH3-30-Encoded Heterosubtypic Antibody.,Wyrzucki A, Dreyfus C, Kohler I, Steck M, Wilson IA, Hangartner L J Virol. 2014 Apr 9. PMID:24719426[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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