A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies
A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies
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DOI：
10.1128/jvi.00685-09
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Wilson, Ian A.
中科院分区：
文献类型：
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作者：
Pejchal, Robert;Gach, Johannes S.;Wilson, Ian A.
人类免疫缺陷病毒（HIV）包膜糖蛋白（gp 41）的近膜外部区域（MPER）对于病毒融合和感染性至关重要，并且是五种已知的广泛中和HIV 1型（HIV-1）抗体中的三种（2F 5、Z13和4 E10）的靶标。在这里，我们报告的晶体结构的Fab片段的Z13 e1，单克隆抗体Z13的亲和力增强的变体，在复合物与12个残基的肽对应的核心表位（（WNWFDITN 677）-N-670）在1.8埃分辨率。结合肽采用由两个串联的垂直螺旋转角组成的S形构象。这种构象与结合到4 E10的重叠MPER肽所采用的α-螺旋结构显著不同。Z13 e1在膜界面处结合到MPER中的肘部，与保守的芳香族化合物（Trp 672和Phe 673）产生相对较少的相互作用，这些芳香族化合物对于4 E10识别至关重要。Z13 e1和4 E10表位结构的比较揭示了构象转换，使得中和可以通过识别主要是两亲性的MPER的不同构象和表面而发生。Z13 e1结构为MPER的动态性质提供了重要的新见解，这可能对膜融合至关重要，并且它对MPER抗体中和HIV-1的机制和HIV-1免疫原的设计具有重要意义。
The membrane-proximal external region (MPER) of the human immunodeficiency virus (HIV) envelope glycoprotein (gp41) is critical for viral fusion and infectivity and is the target of three of the five known broadly neutralizing HIV type 1 (HIV-1) antibodies, 2F5, Z13, and 4E10. Here, we report the crystal structure of the Fab fragment of Z13e1, an affinity-enhanced variant of monoclonal antibody Z13, in complex with a 12-residue peptide corresponding to the core epitope ((WNWFDITN677)-N-670) at 1.8-angstrom resolution. The bound peptide adopts an S-shaped conformation composed of two tandem, perpendicular helical turns. This conformation differs strikingly from the alpha-helical structure adopted by an overlapping MPER peptide bound to 4E10. Z13e1 binds to an elbow in the MPER at the membrane interface, making relatively few interactions with conserved aromatics (Trp672 and Phe673) that are critical for 4E10 recognition. The comparison of the Z13e1 and 4E10 epitope structures reveals a conformational switch such that neutralization can occur by the recognition of the different conformations and faces of the largely amphipathic MPER. The Z13e1 structure provides significant new insights into the dynamic nature of the MPER, which likely is critical for membrane fusion, and it has significant implications for mechanisms of HIV-1 neutralization by MPER antibodies and for the design of HIV-1 immunogens.