Journal Article

Structural basis of coreceptor recognition by HIV-1 envelope spike

Shaik, Md Munan, Lu, Jianming, Chen, Bing, Liao, Maofu, Xu, Chen, Peng, Hanqin, Rits-Volloch, Sophia

2019

Overview

HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160) 3 cleaved to (gp120 and gp41) 3 , interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and 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; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate 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 into host cells and may guide the development of vaccines and therapeutic agents. The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/535 / 631/535/1258/1259 / 82/83 / Allosteric properties / Analysis / Anchoring / Anti-HIV Agents - chemistry / Anti-HIV Agents - metabolism / Automation / Binding Sites / CCR5 protein / CD4 antigen / CD4 Antigens - chemistry / CD4 Antigens - isolation & purification / CD4 Antigens - metabolism / CD4 Antigens - ultrastructure / Cell Line / Cell membranes / Chemical compounds / Chemokine CCL5 - chemistry / Chemokine CCL5 - metabolism / Chemokines / Conformation / Cryoelectron microscopy / Electron microscopy / Genetic aspects / Glycoprotein gp120 / Glycoprotein gp160 / Glycoprotein gp41 / Glycoproteins / Helices / HIV / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - isolation & purification / HIV Envelope Protein gp120 - metabolism / HIV Envelope Protein gp120 - ultrastructure / HIV Envelope Protein gp41 - chemistry / HIV Envelope Protein gp41 - metabolism / HIV Envelope Protein gp41 - ultrastructure / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Inserts / Ligands / Maraviroc - chemistry / Maraviroc - metabolism / Membranes / Microscopy / Models, Molecular / multidisciplinary / Pharmacology / Protein Binding / Protein Conformation / Protein structure / Proteins / Receptors, CCR5 - chemistry / Receptors, CCR5 - isolation & purification / Receptors, CCR5 - metabolism / Receptors, CCR5 - ultrastructure / Receptors, HIV - antagonists & inhibitors / Receptors, HIV - chemistry / Receptors, HIV - metabolism / Receptors, HIV - ultrastructure / Science / Science (multidisciplinary) / Signal transduction / Structure / Trimers / Vaccines / Viruses