Sethi Dhruv K, Agarwal Anupriya, Manivel Venkatasamy, Rao Kanury V S, Salunke Dinakar M
National Institute of Immunology, New Delhi 110067, India.
Immunity. 2006 Apr;24(4):429-38. doi: 10.1016/j.immuni.2006.02.010.
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.
通过使用种系抗体36-65，研究了种系抗体中初次抗体应答的混杂性与构象灵活性之间的相关性。对36-65 Fab与三种独立的十二肽进行晶体学分析，为抗体多样性的产生提供了机制性见解。虽然四个无抗原的Fab分子对抗体互补决定区（CDR）的构象库进行了定量描述，但与结构多样的肽表位结合的三个Fab分子表现出共同的抗原结合部位构象。每个肽在抗原结合位点内显示出空间上不同的足迹。然而，可以识别出一种涉及两个共享残基的构象特异性锁，这两个残基也与半抗原结合有关。与半抗原不同，这些肽与经历体细胞突变的残基相互作用，这表明在亲和力成熟过程中排除“非特异性”抗原的一种可能机制。在种系抗体的共同抗原结合部位构象内观察到的不同表位的多种结合模式揭示了一种简单而优雅的机制，用于扩展初次抗体库。
