期刊
EMBO JOURNAL
卷 27, 期 19, 页码 2592-2602出版社
WILEY
DOI: 10.1038/emboj.2008.179
关键词
germline antibody; human cytomegalovirus immunological memory; structure; thermodynamics
资金
- National Institutes of Health, National Center for Research Resources [RR0077-7]
- CIHR-UBC Strategic Training Program
- Canadian Institutes of Health Research [MOP-179283]
Immunoglobulin genes are generated somatically through specialized mechanisms resulting in a vast repertoire of antigen-binding sites. Despite the stochastic nature of these processes, the V-genes that encode most of the antigen-combining site are under positive evolutionary selection, raising the possibility that V-genes have been selected to encode key structural features of binding sites of protective antibodies against certain pathogens. Human, neutralizing antibodies to human cytomegalovirus that bind the AD-2S1 epitope on its gB envelope protein repeatedly use a pair of well-conserved, germline V-genes IGHV3-30 and IGKV3-11. Here, we present crystallographic, kinetic and thermodynamic analyses of the binding site of such an antibody and that of its primary immunoglobulin ancestor. These show that these germline V-genes encode key side chain contacts with the viral antigen and thereby dictate key structural features of the hypermutated, high-affinity neutralizing antibody. V-genes may thus encode an innate, protective immunological memory that targets vulnerable, invariant sites on multiple pathogens.
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