Epitopes described in "Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody."

Article Authors:Aaron G Schmidt; Huafeng Xu; Amir R Khan; Timothy O'Donnell; Surender Khurana; Lisa R King; Jody Manischewitz; Hana Golding; Pirada Suphaphiphat; Andrea Carfi; Ethan C Settembre; Philip R Dormitzer; Thomas B Kepler; Ruijun Zhang; M Anthony Moody; Barton F Haynes; Hua-Xin Liao; David E Shaw; Stephen C Harrison
Article Title:Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.
Reference Detail
Reference ID:1025297
Abstract: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.
Affiliations:Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Reference Type:Literature
PubMed ID:23175789
Journal:Proc Natl Acad Sci U S A
Journal Volume:110
Article Pages:264-9
Journal ISSN:0027-8424
Article Chemical List:Antibodies, Neutralizing;Antibodies, Viral;Immunoglobulin Fab Fragments;Immunoglobulin Variable Region;Influenza Vaccines
Article MeSH List:Amino Acid Sequence; Antibodies, Neutralizing(chemistry; genetics); Antibodies, Viral(genetics); B-Lymphocytes(immunology); Binding Sites, Antibody(genetics); Crystallography, X-Ray; Evolution, Molecular; Immunoglobulin Fab Fragments(chemistry); Immunoglobulin Variable Region(genetics); Influenza Vaccines(immunology); Models, Molecular; Molecular Dynamics Simulation; Molecular Sequence Data; Orthomyxoviridae(immunology)
Curation Last Updated:2015-06-05 03:45:22