Structural basis of coreceptor recognition by HIV-1 envelope spike

Abstract

HIV-1 envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3] interacts with primary receptor CD4 and coreceptor (e.g. chemokine receptor CCR5 or CXCR4) to allow viral entry by catalyzing fusion of viral and target cell membranes. Encounter of gp120 with the coreceptor was thought to be the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-EM structure, at 3.9Å resolution, of a full-length gp120 in complex with a soluble CD4 and an unmodified human CCR5. The V3 loop of gp120 inserts into the chemokine binding pocket formed by seven transmembrane helices of CCR5, which adopts an inactive conformation, while the N-terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41, but it brings the Env trimer close to the target membrane. The extended N-terminus of gp120, gripped by gp41 in the prefusion or CD4-bound Env trimer, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to promote fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry and may guide development of vaccines and therapeutics.