title: Structural insights into the evolution of an antibody combining site.
abstract: The crystal structures of a germline antibody Fab fragment and its complex with hapten have been solved at 2.1 A resolution. These structures are compared with the corresponding crystal structures of the affinity-matured antibody, 48G7, which has a 30,000 times higher affinity for hapten as a result of nine replacement somatic mutations. Significant changes in the configuration of the combining site occur upon binding of hapten to the germline antibody, whereas hapten binds to the mature antibody by a lock-and-key fit mechanism. The reorganization of the combining site that was nucleated by hapten binding is further optimized by somatic mutations that occur up to 15  from bound hapten. These results suggest that the binding potential of the primary antibody repertoire may be significantly expanded by the ability of germline antibodies to adopt more than one combining-site configuration, with both antigen binding and somatic mutation stabilizing the configuration with optimal hapten complementarity.
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Wedemayer
authors.forename: P A
authors.initials: PA
authors.lastname: Patten
authors.forename: L H
authors.initials: LH
authors.lastname: Wang
authors.forename: P G
authors.initials: PG
authors.lastname: Schultz
authors.forename: R C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D017151:Antibodies, Catalytic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000915:Antibody Affinity; D000916:Antibody Diversity; D000936:Antigen-Antibody Complex; D000937:Antigen-Antibody Reactions; D001665:Binding Sites; D001666:Binding Sites, Antibody; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006241:Haptens / Q000276:immunology; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D017151:Antibodies, Catalytic; D000936:Antigen-Antibody Complex; D006241:Haptens; D007140:Immunoglobulin Fab Fragments