Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses
Harshbarger, Wayne D. ; Deming, Derrick ; Lockbaum, Gordon J. ; Attatippaholkun, Nattapol ; Kamkaew, Maliwan ; Hou, Shurong ; Somasundaran, Mohan ; Wang, Jennifer P. ; Finberg, Robert W. ; Zhu, Quan Karen ... show 2 more
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UMass Chan Affiliations
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Keywords
Antibodies, Viral
Epitopes
Hemagglutinin Glycoproteins, Influenza Virus
Humans
Influenza A virus
Influenza Vaccines
Influenza, Human
Antibodies
Neutralizing
Antibodies
Viral
Epitopes
Hemagglutinin Glycoproteins
Influenza Virus
Humans
Influenza A virus
Influenza Vaccines
Influenza
Human
Amino Acids, Peptides, and Proteins
Influenza Virus Vaccines
Medicinal Chemistry and Pharmaceutics
Medicinal-Pharmaceutical Chemistry
Pharmaceutics and Drug Design
Structural Biology
Virology
Viruses
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Abstract
Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.
Source
Harshbarger WD, Deming D, Lockbaum GJ, Attatippaholkun N, Kamkaew M, Hou S, Somasundaran M, Wang JP, Finberg RW, Zhu QK, Schiffer CA, Marasco WA. Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses. Nat Commun. 2021 Jan 25;12(1):559. doi: 10.1038/s41467-020-20879-6. PMID: 33495478; PMCID: PMC7835374. Link to article on publisher's site