Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.
Journal Article (Journal Article)
Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.
Full Text
Duke Authors
Cited Authors
- Schmidt, AG; Xu, H; Khan, AR; O'Donnell, T; Khurana, S; King, LR; Manischewitz, J; Golding, H; Suphaphiphat, P; Carfi, A; Settembre, EC; Dormitzer, PR; Kepler, TB; Zhang, R; Moody, MA; Haynes, BF; Liao, H-X; Shaw, DE; Harrison, SC
Published Date
- January 2, 2013
Published In
Volume / Issue
- 110 / 1
Start / End Page
- 264 - 269
PubMed ID
- 23175789
Pubmed Central ID
- PMC3538208
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1218256109
Language
- eng
Conference Location
- United States