Structural basis of coreceptor recognition by HIV-1 envelope spike

Md Munan Shaik, Hanqin Peng, Jianming Lu, Sophia Rits-Volloch, Chen Xu, Maofu Liao and Bing Chen ()
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Md Munan Shaik: Harvard Medical School
Hanqin Peng: Harvard Medical School
Jianming Lu: Codex BioSolutions
Sophia Rits-Volloch: Harvard Medical School
Chen Xu: University of Massachusetts Medical School
Maofu Liao: Harvard Medical School
Bing Chen: Harvard Medical School

Nature, 2019, vol. 565, issue 7739, 318-323

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-018-0804-9

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