9 Å Structure of Trimeric HIV-1 Envelope Glycoprotein in an Activated State

Abstract

The HIV envelope glycoprotein (Env) binds to CD4 and a chemokine co-receptor to mediate fusion of viral and target-cell membranes required for infection. We have previously shown that the unbound Env is a mushroom-shaped trimer with a stem composed of three membrane-anchored gp41 subunits capped by three gp120 subunits. We also showed that binding to CD4 and the co-receptor site binding Fab 17b leads to a significant outward movement of gp120 and to a rearrangement of density in gp41, resulting in an “open” conformation. Soluble constructs bearing the complete ectodomain of Env (gp140) display conformations that closely resemble the structure of native unliganded trimeric Env, and importantly, show identical ligand-induced transitions. Here we show that a key structural signature of the open Env conformation is a three-helix motif composed of α-helical segments derived from highly conserved, non-glycosylated N-terminal regions of the gp41 trimer. The three N-terminal helices in this novel, pre-fusion intermediate are much less compactly packed than in the post-fusion, six-helix bundle state. These findings suggest a new structural template for designing immunogens that can elicit antibodies targeting HIV at a vulnerable, pre-entry stage.View Large Image | View Hi-Res Image | Download PowerPoint Slide