Structural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs.
Structural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs.
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通过具有交叉反应性的 HIV-1 中和抗体与含有独特基序的 CDR-H2 和 H3 来模拟 CD4。
DOI：
10.1016/j.jmb.2005.12.062
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发表时间：
2006
影响因子：
5.6
通讯作者：
Ji,Xinhua
中科院分区：
文献类型：
--
作者：
Prabakaran,Ponraj;Gan,Jianhua;Wu,You-Qiang;Zhang,Mei-Yun;Dimitrov,DimiterS;Ji,Xinhua
人类免疫缺陷病毒（HIV）进入细胞是通过其包膜糖蛋白（Env）gp 120与受体CD 4结合启动的。与gp 120上的CD 4结合位点（CD 4 bs）重叠的表位结合的抗体可以通过与细胞相关的CD 4竞争来防止HIV进入;它们竞争胜过CD 4的能力是其中和效力的主要决定因素，并且与它们的亲合力成比例。中和的广度和抗体抗性病毒出现的可能性主要取决于其表位的结构。由于CD 4 bs是高度保守的，因此可以合理地假设，紧密模拟CD 4的抗体可以表现出相对广泛的交叉反应性和防止耐药病毒出现的高概率。以前，在寻找模拟CD 4或辅助受体的抗体时，我们鉴定并表征了广泛交叉反应的HIV中和CD 4 bs人单克隆抗体（hmAb），m18。在这里，我们描述了Fab m18在2.03 nm分辨率的晶体结构，它揭示了重链互补决定区（CDR）2和3（H2和H3）的独特构象。H2是高度膨胀的，并且在所有四种典型结构中观察到缺乏交联链间氢键。H3长17.5 μ m，刚性，形成一个延伸的β-折叠，装饰有一个α-转角基序，顶端有一个苯丙氨酸-异亮氨酸叉。它与CD 4第一结构域D1的IG CDR 2样C′C″区具有惊人的相似性，后者主导CD 4与gp 120的结合。对接模拟表明m18表位和gp 120上的CD 4 bs之间具有显著的相似性。Fab m18不增强CD 4诱导的（CD 4 i）抗体的结合，也不诱导HIV Env介导的CD 4非依赖性融合。因此，基于m18表位结构的疫苗免疫原不太可能引发可以增强感染的抗体。该结构也可以作为设计新型高效HIV进入抑制剂的基础。
Human immunodeficiency virus (HIV) entry into cells is initiated by the binding of its envelope glycoprotein (Env) gp120 to receptor CD4. Antibodies that bind to epitopes overlapping the CD4-binding site (CD4bs) on gp120 can prevent HIV entry by competing with cell-associated CD4; their ability to outcompete CD4 is a major determinant of their neutralizing potency and is proportional to their avidity. The breadth of neutralization and the likelihood of the emergence of antibody-resistant virus are critically dependent on the structure of their epitopes. Because CD4bs is highly conserved, it is reasonable to hypothesize that antibodies closely mimicking CD4 could exhibit relatively broad cross-reactivity and a high probability of preventing the emergence of resistant viruses. Previously, in a search for antibodies that mimic CD4 or the co-receptor, we identified and characterized a broadly cross-reactive HIV-neutralizing CD4bs human monoclonal antibody (hmAb), m18. Here, we describe the crystal structure of Fab m18 at 2.03Å resolution, which reveals unique conformations of heavy chain complementarity-determining regions (CDRs) 2 and 3 (H2 and H3). H2 is highly bulged and lacks cross-linking interstrand hydrogen bonds observed in all four canonical structures. H3 is 17.5Å long and rigid, forming an extended β-sheet decorated with an α-turn motif bearing a phenylalanine-isoleucine fork at the apex. It shows striking similarity to the Ig CDR2-like C′C″ region of the CD4 first domain D1 that dominates the binding of CD4 to gp120. Docking simulations suggest significant similarity between the m18 epitope and the CD4bs on gp120. Fab m18 does not enhance binding of CD4-induced (CD4i) antibodies, nor does it induce CD4-independent fusion mediated by the HIV Env. Thus, vaccine immunogens based on the m18 epitope structure are unlikely to elicit antibodies that could enhance infection. The structure can also serve as a basis for the design of novel, highly efficient inhibitors of HIV entry.