gp41: HIV's shy protein

Abstract

The first X-ray crystal structures of gp41, the protein that mediates fusion of HIV-1 to target cells, were solved in the mid-1990s. The structures provide a foundation for understanding viral entry and the mechanism of action of compounds that block fusion. The first fusion inhibitor has recently entered the clinic, and the hope is that more potent and broadly active compounds, based on molecular design, will follow.

Figure 1. The conformations of HIV-1 gp41 before, during and after the fusion of the viral and host-cell membranes.

The HIV-1 envelope spike is a putative trimer of gp120-gp41 heterodimers. (a) Before fusion. In the native, untriggered conformation, the ectodomain (extraviral portion) of gp41 is largely cloaked by gp120 (transparent here). The structural details of this native configuration are not well elucidated. (b) Fusion intermediate(s). Upon binding CD4 and coreceptor, gp120 undergoes conformational changes that expose gp41 and activate the fusion machinery, notably the N-HR regions and the fusion peptide (FP). gp41 is probably in a somewhat extended arrangement in which the N-HR region of three gp41 molecules form an α-helical bundle, positioning the fusion peptides for insertion into the host-cell membrane. The C-HR region of gp41 is drawn here without defined secondary structure, but some models show it in an α-helical conformation. gp41-targeting fusion inhibitors such as T20 act on the fusion-intermediate conformation(s) of gp41 to inhibit six-helix bundle formation. (c) After fusion. Fusion seems to coincide with chain reversal, or 'jackknifing', such that the antiparallel N-HR and C-HR regions form a six-helix bundle, represented here by the structure of Weissenhorn et al.. Deborah Maizels