TY - JOUR
T1 - Differential Epitope Positioning within the Germline Antibody Paratope Enhances Promiscuity in the Primary Immune Response
AU - Sethi, Dhruv K.
AU - Agarwal, Anupriya
AU - Manivel, Venkatasamy
AU - Rao, Kanury V.S.
AU - Salunke, Dinakar M.
N1 - Funding Information:
We would like to thank Dr. Tim Manser for gift of the anti-Ars hybridoma, H.S. Sarna and Z. Siddiqui for technical assistance, and Drs. T.P. Singh, S. Rath, and K. Suguna for useful discussions. Financial support from the Department of Biotechnology and the Indian Council of Medical Research, Government of India is gratefully acknowledged.
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=33645990894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645990894&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2006.02.010
DO - 10.1016/j.immuni.2006.02.010
M3 - Article
C2 - 16618601
AN - SCOPUS:33645990894
SN - 1074-7613
VL - 24
SP - 429
EP - 438
JO - Immunity
JF - Immunity
IS - 4
ER -