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Elife. 2018 Mar 21;7. pii: e34271. doi: 10.7554/eLife.34271.

HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations.

Author information

1
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States.
2
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States.
3
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States.
4
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States.
5
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, United States.

Abstract

HIV-1 entry into cells requires binding of the viral envelope glycoprotein (Env) to receptor CD4 and coreceptor. Imaging of individual Env molecules on native virions shows Env trimers to be dynamic, spontaneously transitioning between three distinct well-populated conformational states: a pre-triggered Env (State 1), a default intermediate (State 2) and a three-CD4-bound conformation (State 3), which can be stabilized by binding of CD4 and coreceptor-surrogate antibody 17b. Here, using single-molecule Fluorescence Resonance Energy Transfer (smFRET), we show the default intermediate configuration to be asymmetric, with individual protomers adopting distinct conformations. During entry, this asymmetric intermediate forms when a single CD4 molecule engages the trimer. The trimer can then transition to State 3 by binding additional CD4 molecules and coreceptor.

KEYWORDS:

HIV-1 Envelope; Single molecule FRET; infectious disease; microbiology; molecular biophysics; structural biology; virus; virus entry

PMID:
29561264
PMCID:
PMC5896952
DOI:
10.7554/eLife.34271
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

XM, ML, JG, DT, XH, ZZ, HZ, RA, JA, SB, PK, JM No competing interests declared, WM Patent applications pertaining to this work are U.S. Patent Application 13/202,351, Methods and Compositions for Altering Photophysical Properties of Fluorophores via Proximal Quenching (S.C.B., Z.Z.); U.S. Patent Application 14/373,402 Dye Compositions, Methods of Preparation, Conjugates Thereof, and Methods of Use (S.C.B., Z.Z.); and International and US Patent Application PCT/US13/42249 Reagents and Methods for Identifying Anti-HIV Compounds (S.C.B., J.B.M., W.M.). S.C.B. is a co-founder of Lumidyne Corporation

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