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Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
Journal article   Open access   Peer reviewed

Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET

Maolin Lu, Xiaochu Ma, Luis R Castillo-Menendez, Jason Gorman, Nirmin Alsahafi, Utz Ermel, Daniel S Terry, Michael Chambers, Dongjun Peng, Baoshan Zhang, …
Nature (London), v 568(7752), pp 415-419
Apr 2019
DOI: https://doi.org/10.1038/s41586-019-1101-y
PMID: 30971821
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc6655592View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animals Antibodies, Neutralizing - immunology Cattle Disulfides - chemistry env Gene Products, Human Immunodeficiency Virus - chemistry env Gene Products, Human Immunodeficiency Virus - genetics env Gene Products, Human Immunodeficiency Virus - immunology Fluorescence Resonance Energy Transfer HEK293 Cells HIV-1 - chemistry HIV-1 - genetics HIV-1 - immunology Humans Models, Molecular Mutation Protein Conformation Protein Multimerization Protein Stability Single Molecule Imaging
The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic . Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3) . It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers) . Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1 strain in complex with the antibody PGT151 . Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pre-triggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies-and thus of interest for the design of immunogens-remains unknown.

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Domestic collaboration
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Web of Science research areas
Virology
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