Structural basis of coreceptor recognition by HIV-1 envelope spike

Article

关键词: IMMUNODEFICIENCY-VIRUS TYPE-1;    CRYO-EM STRUCTURE;    CHEMOKINE RECEPTORS;    CRYSTAL-STRUCTURE;    MUTATIONAL PATHWAYS;    AMINO-TERMINUS;    SMALL-MOLECULE;    CCR5;    GP120;    CXCR4;   

DOI  :  10.1038/s41586-018-0804-9

来源: SCIE

【 摘 要 】

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 angstrom 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.

【 授权许可】

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