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Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion

Wang, Haoqing and Barnes, Christopher O. and Yang, Zhi and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2018) Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. Cell Host & Microbe, 24 (4). pp. 579-592. ISSN 1931-3128. PMCID PMC6185872. https://resolver.caltech.edu/CaltechAUTHORS:20181010-142117602

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Abstract

HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4-induced rearrangements that result in V1V2 displacement and formation of a 4-stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor-induced Env changes and inform design of therapeutics disrupting viral entry.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.chom.2018.09.003DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185872/PubMed CentralArticle
ORCID:
AuthorORCID
Wang, Haoqing0000-0003-0277-3018
Barnes, Christopher O.0000-0003-2754-5951
Yang, Zhi0000-0001-8680-3784
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 3 July 2018, Revised 20 July 2018, Accepted 5 September 2018, Available online 10 October 2018. We thank Zhiheng Yu, Chuan Hong, Rick Huang, and Dan Shi (Janelia Farm) for assistance with cryo-EM data collection and motion correction; Andrey Malyutin and Songye Chen for assistance with grid preparation; Jost Vielmetter and the Caltech Protein Expression Center for transfections and protein expression; Al Cupo and John Moore (Weill Cornell Medical College) for the stable cell line expressing B41 SOSIP; James Robinson (Tulane University) for the 21c hybridoma; and members of the Bjorkman and Grant Jensen laboratories for helpful discussions and critical reading of the manuscript. This research was supported by NIH grant 2 P50 GM082545-06 (to P.J.B.), National Institute of Allergy and Infectious Diseases of the NIH grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), and the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery grant 1040753 (to P.J.B. and M.C.N.). M.C.N. is an HHMI investigator. Research support was also provided by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund (C.O.B.). We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support electron microscopy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Author Contributions: H.W., C.O.B., M.C.N., and P.J.B. designed the research; H.W. and C.O.B. performed research; H.W., C.O.B., Z.Y., and P.J.B. analyzed data; and H.W., C.O.B., and P.J.B. wrote the paper. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIH2 P50 GM082545-06
NIHP01 AI100148
Bill and Melinda Gates Foundation1040753
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Subject Keywords:HIV-1 envelope; CD4; viral membrane fusion; cryoelectron microscopy
Issue or Number:4
PubMed Central ID:PMC6185872
Record Number:CaltechAUTHORS:20181010-142117602
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181010-142117602
Official Citation:Haoqing Wang, Christopher O. Barnes, Zhi Yang, Michel C. Nussenzweig, Pamela J. Bjorkman, Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion, Cell Host & Microbe, Volume 24, Issue 4, 2018, Pages 579-592.e4, ISSN 1931-3128, https://doi.org/10.1016/j.chom.2018.09.003. (http://www.sciencedirect.com/science/article/pii/S1931312818304876)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90234
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Oct 2018 06:03
Last Modified:03 Aug 2020 22:17

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