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Nature. 2019 Jan;565(7739):318-323. doi: 10.1038/s41586-018-0804-9. Epub 2018 Dec 12.

Structural basis of coreceptor recognition by HIV-1 envelope spike.

Author information

1
Division of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
3
Codex BioSolutions, Gaithersburg, MD, USA.
4
Xiamen Amoytop Biotech, Xiamen, China.
5
Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
7
Division of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. bchen@crystal.harvard.edu.
8
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. bchen@crystal.harvard.edu.

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.

Comment in

PMID:
30542158
PMCID:
PMC6391877
DOI:
10.1038/s41586-018-0804-9
[Indexed for MEDLINE]
Free PMC Article

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