Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope
Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope
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DOI：
10.1128/jvi.78.19.10724-10737.2004
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发表时间：
2004-10-01
影响因子：
5.4
通讯作者：
Kwong, PD
中科院分区：
文献类型：
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作者：
Ofek, G;Tang, M;Kwong, PD
人类免疫缺陷病毒1型（HIV-1）的gp 41包膜糖蛋白的胞外域的近膜区域是迄今分离的5种广泛中和抗HIV-1抗体中的3种的靶标。我们已经确定了晶体结构的抗原结合片段的这些抗体之一，2F 5，在复杂的7聚体，11聚体，和17聚体肽的gp 41膜近端区域，在2.0-，2.1-，和2.24分辨率，分别。这些结构揭示了一种延伸的gp 41构象，其长度超过30埃。与抗体的五个互补决定区以及非多态性区进行接触。gp 41表位的仅一个排他的带电面被2F 5结合，而疏水的非结合面可能由于被胞外域的其他部分遮挡而被隐藏。这些结构揭示了2F 5抗体被独特地构建为结合至接近膜表面的表位，并且以大部分不受大规模空间位阻影响的方式结合。蛋白脂质体的生化研究证实了脂质膜和疏水环境在2F 5结合以及4 E10结合中的重要性，4 E10是另一种识别gp 41近膜区的广泛中和抗体。基于这些结构和生化结果，提出了用于引发2F 5-和4 E10-样广泛中和抗HIV-1抗体的免疫策略。
The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.24 resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 Angstrom in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.