结构基础上的交叉反应的基因相关的人类抗 hiv-1 mabs: implications for design 的 v3 为基础的免疫原。
Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens.
机构信息
Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.
出版信息
Structure. 2009 Nov 11;17(11):1538-46. doi: 10.1016/j.str.2009.09.012.
Abstract
Human monoclonal antibodies 447-52D and 537-10D, both coded by the VH3 gene and specific for the third variable region (V3) of the HIV-1 gp120, were found to share antigen-binding structural elements including an elongated CDR H3 forming main-chain interactions with the N terminus of the V3 crown. However, water-mediated hydrogen bonds and a unique cation-pi sandwich stacking allow 447-52D to be broadly reactive with V3 containing both the GPGR and GPGQ crown motifs, while the deeper binding pocket and a buried Glu in the binding site of 537-10D limit its reactivity to only V3 containing the GPGR motif. Our results suggest that the design of immunogens for anti-V3 antibodies should avoid the Arg at the V3 crown, as GPGR-containing epitopes appear to select for B cells making antibodies of narrower specificity than V3 that carry Gln at this position.
摘要
人类单克隆抗体 447-52D 和 537-10D 均由 VH3 基因编码，特异性针对 HIV-1 gp120 的第三个可变区 (V3)。它们被发现具有共享的抗原结合结构元件，包括形成与 V3 冠部 N 端主链相互作用的长 CDR H3。然而，水介导的氢键和独特的阳离子-π 夹心堆积允许 447-52D 广泛反应于包含 GPGR 和 GPGQ 冠基序的 V3，而 537-10D 的结合位点中的更深的结合口袋和埋藏的 Glu 限制了其仅对包含 GPGR 基序的 V3 的反应性。我们的结果表明，用于抗-V3 抗体的免疫原的设计应避免 V3 冠部的 Arg，因为含有 GPGR 的表位似乎选择产生比 V3 具有更窄特异性的 B 细胞，而 V3 在该位置携带 Gln。
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