Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41
Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41
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DOI：
10.1016/j.immuni.2004.12.011
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发表时间：
2005-02-01
期刊：
影响因子：
32.4
通讯作者：
Wilson, IA
中科院分区：
文献类型：
--
作者：
Cardoso, RMF;Zwick, MB;Wilson, IA
广泛中和HIV-1的单克隆抗体是罕见的，但对疫苗设计是非常宝贵的。4 E10是已知的最广泛的中和抗体，并且识别gp 41的近膜区中的连续和高度保守的表位。在2.2埃分辨率下测定与含有gp 41核心表位的13-残基肽（NWFDIT）复合的Fab 4 E10的晶体结构。结合肽采用螺旋构象，其中关键接触残基Trp（P672）、Phe（P673）、Ile（P675）和Thr（P676）映射到螺旋的一个面。该肽结合在疏水口袋中，该疏水口袋可以模拟其与宿主细胞膜的潜在相互作用。该抗体的长CDR H3以一定的方向延伸超出结合的肽，这表明当4 E10与其近膜表位结合时，其顶点可以接触病毒膜。这些结构的见解应有助于设计免疫原，以引发4 E10样中和反应。
Broadly neutralizing monoclonal antibodies to HIV-1 are rare but invaluable for vaccine design. 4E10 is the broadest neutralizing antibody known and recognizes a contiguous and highly conserved epitope in the membrane-proximal region of gp41. The crystal structure of Fab 4E10 was determined at 2.2 Angstrom resolution in complex with a 13-residue peptide containing the gp41 core epitope (NWFDIT). The bound peptide adopts a helical conformation in which the key contact residues, Trp(P672), Phe(P673), Ile(P675), and Thr(P676), map to one face of the helix. The peptide binds in a hydrophobic pocket that may emulate its potential interaction with the host cell membrane. The long CDR H3 of the antibody extends beyond the bound peptide in an orientation that suggests that its apex could contact the viral membrane when 4E10 is bound to its membrane-proximal epitope. These structural insights should assist in the design of immunogens to elicit 4E10-like neutralizing responses.