Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing Fabs

被引:117
作者
Stanfield, RL
Cabezas, E
Satterthwait, AC
Stura, EA
Profy, AT
Wilson, IA
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Repligen Corp, Needham, MA 02194 USA
[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
关键词
antibody-peptide complex; Fab fragment; HIV-1; vaccine; X-ray crystallography;
D O I
10.1016/S0969-2126(99)80020-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: The third hypervariable (V3) loop of HIV-1 gp120 has been termed the principal neutralizing determinant (PND) of the virus and is involved in many aspects of virus infectivity. The V3 loop is required for viral entry into the cell via membrane fusion and is believed to interact with cell surface chemokine receptors on T cells and macrophages. Sequence changes in V3 can affect chemokine receptor usage, and can, therefore, modulate which types of cells are infected. Antibodies raised against peptides with V3 sequences can neutralize laboratory-adapted strains of the virus and inhibit syncytia formation, Fab fragments of these neutralizing antibodies in complex with V3 loop peptides have been studied by X-ray crystallography to determine the conformation of the V3 loop. Results: We have determined three crystal structures of Fab 58.2, a broadly neutralizing antibody, in complex with one linear and two cyclic peptides the amino acid sequence of which comes from the MN isolate of the gp120 V3 loop. Although the peptide conformations are very similar for the linear and cyclic forms, they differ from that seen for the identical peptide bound to a different broadly neutralizing antibody, Fab 59.1, and for a similar peptide bound to the MN-specific Fab 50.1. The conformational difference in the peptide is localized around residues Gly-Pro-Gly-Arg, which are highly conserved in different HIV-1 isolates and are predicted to adopt a type II beta turn. Conclusions: The V3 loop can adopt at least two different conformations for the highly conserved Gly-Pro-Gly-Arg sequence at the tip of the loop. Thus, the HIV-1 V3 loop has some inherent conformational flexibility that may relate to its biological function.
引用
收藏
页码:131 / 142
页数:12
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