期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 25, 期 9, 页码 814-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0113-x
关键词
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资金
- Wellcome Trust [105278, 203852, 203141]
- Medical Research Council [MR/L009528/1]
- National Institutes of Health Oxford-Cambridge Fellowship
- Nuffield Department of Medicine
- MRC [MR/L009528/1] Funding Source: UKRI
Little is known about the intermolecular dynamics and stoichiometry of the interactions of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) protein with its receptors and co-receptors on the host cell surface. Here we analyze time-resolved HIV-1 Env interactions with T-cell surface glycoprotein CD4 (CD4) and C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) on the surface of cells, by combining multicolor super-resolution localization microscopy (direct stochastic optical reconstruction microscopy) with fluorescence fluctuation spectroscopy imaging. Utilizing the primary isolate JR-FL and laboratory HXB2 strains, we reveal the time-resolved stoichiometry of CD4 and CCR5 or CXCR4 in the prefusion complex with HIV-1 Env. The HIV-1 Env pre-fusion dynamics for both R5-and X4-tropic strains consists of a three-step mechanism, which seems to differ in stoichiometry. Analyses with the monoclonal HIV-1-neutralizing antibody b12 indicate that the mechanism of inhibition differs between JR-FL and HXB2 Env. The molecular insights obtained here identify assemblies of HIV-1 Env with receptors and co-receptors as potential novel targets for inhibitor design.
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