title: Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary immune response.
abstract: Correlation between the promiscuity of the primary antibody response and conformational flexibility in a germline antibody was addressed by using germline antibody 36-65. Crystallographic analyses of the 36-65 Fab with three independent dodecapeptides provided mechanistic insights into the generation of antibody diversity. While four antigen-free Fab molecules provided a quantitative description of the conformational repertoire of the antibody CDRs, three Fab molecules bound to structurally diverse peptide epitopes exhibited a common paratope conformation. Each peptide revealed spatially different footprints within the antigen-combining site. However, a conformation-specific lock involving two shared residues, which were also associated with hapten binding, was discernible. Unlike the hapten, the peptides interacted with residues that undergo somatic mutations, suggesting a possible mechanism for excluding "nonspecific" antigens during affinity maturation. The observed multiple binding modes of diverse epitopes within a common paratope conformation of a germline antibody reveal a simple, yet elegant, mechanism for expanding the primary antibody repertoire.
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Dhruv K
authors.initials: DK
authors.lastname: Sethi
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.forename: Venkatasamy
authors.initials: V
authors.lastname: Manivel
authors.forename: Kanury V S
authors.initials: KV
authors.lastname: Rao
authors.forename: Dinakar M
authors.initials: DM
authors.lastname: Salunke
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology*; D000916:Antibody Diversity; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D020836:Protein Structure, Quaternary
chemical_list: D000906:Antibodies; D018985:Epitopes, B-Lymphocyte; D007140:Immunoglobulin Fab Fragments