Conformational rearrangements required of the V3 loop of HIV‐1 gp120 for proteolytic cleavage and infection

FEBS Letters

Padmanabhan, Kaillathe²  Kahn, Michael³  Tulinsky, Alexander²  Lin, Zhaolan¹  Johnson, Michael E.¹ 

[1] Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street (m/c 781), Chicago, IL 60612-7230, USA;Department of Chemistry, Michigan State University, East Lansing, MI 48824-1322, USA;Department of Pathobiology, University of Washington, Seattle, WA 98195, USA

关键词: AIDS;    Thrombin recognition motif;    β-Turn;    Molecular modeling;    Factor Xa;   

DOI  :  10.1016/0014-5793(94)80618-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

HIV gp120 is specifically cleaved at a single site in the V₃ loop between Arg³¹⁵ and Ala³¹⁶ by thrombin. Previous observations by others have indicated that binding to CD4 enhances the rate of V₃ loop cleavage, and that this cleavage is a prerequisite for HIV infection. Other observations also suggest that the cleavage site is in a type II β-turn centered at Pro³¹³-Gly³¹⁴. However, our docking experiments indicate that this conformation cannot dock to thrombin and other trypsin-like serine proteases. Thus, based on the thrombin-bound conformation of peptide substrates, we propose that CD4 binding, at a site remote from the V₃ loop, induces and stabilizes a trans to cis isomerization of the highly conserved residue Pro³¹³, and that this conformational shift is a prerequisite for cleavage by a ‘thrombin-like’ cellular pro tease and subsequent infection.

【 授权许可】

Unknown