Structural definition of a conserved neutralization epitope on HIV-1 gp120.
Zhou, Tongqing 1; Xu, Ling 1; Dey, Barna 1; Hessell, Ann J. 3; Van Ryk, Donald 2; Xiang, Shi-Hua 4; Yang, Xinzhen 4; Zhang, Mei-Yun 5; Zwick, Michael B. 3; Arthos, James 2; Burton, Dennis R. 3; Dimitrov, Dimiter S. 5; Sodroski, Joseph 4; Wyatt, Richard 1; Nabel, Gary J. 1; Kwong, Peter D. 1
[Article]
Nature.
445(7129):732-737, February 15, 2007.
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The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.
(C) 2007 Nature Publishing Group