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Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Wang, Haoqing and Cohen, Alexander A. and Galimidi, Rachel P. and Gristick, Harry B. and Jensen, Grant J. and Bjorkman, Pamela J. (2016) Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop. Proceedings of the National Academy of Sciences of the United States of America, 113 (46). E7151-E7158. ISSN 0027-8424. PMCID PMC5135367. http://resolver.caltech.edu/CaltechAUTHORS:20161101-072102928

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Abstract

The HIV-1 envelope (Env) glycoprotein, a trimer of gp120–gp41 heterodimers, relies on conformational flexibility to function in fusing the viral and host membranes. Fusion is achieved after gp120 binds to CD4, the HIV-1 receptor, and a coreceptor, capturing an open conformational state in which the fusion machinery on gp41 gains access to the target cell membrane. In the well-characterized closed Env conformation, the gp120 V1V2 loops interact at the apex of the Env trimer. Less is known about the structure of the open CD4-bound state, in which the V1V2 loops must rearrange and separate to allow access to the coreceptor binding site. We identified two anti–HIV-1 antibodies, the coreceptor mimicking antibody 17b and the gp120–gp41 interface-spanning antibody 8ANC195, that can be added as Fabs to a soluble native-like Env trimer to stabilize it in a CD4-bound conformation. Here, we present an 8.9-Å cryo-electron microscopy structure of a BG505 Env–sCD4–17b–8ANC195 complex, which reveals large structural rearrangements in gp120, but small changes in gp41, compared with closed Env structures. The gp120 protomers are rotated and separated in the CD4-bound structure, and the three V1V2 loops are displaced by ∼40 Å from their positions at the trimer apex in closed Env to the sides of the trimer in positions adjacent to, and interacting with, the three bound CD4s. These results are relevant to understanding CD4-induced conformational changes leading to coreceptor binding and fusion, and HIV-1 Env conformational dynamics, and describe a target structure relevant to drug design and vaccine efforts.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1615939113 DOIArticle
http://www.pnas.org/content/113/46/E7151PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1615939113/-/DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135367/PubMed CentralArticle
ORCID:
AuthorORCID
Wang, Haoqing0000-0003-0277-3018
Jensen, Grant J.0000-0003-1556-4864
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2016 National Academy of Sciences. Contributed by Pamela J. Bjorkman, September 24, 2016 (sent for review September 9, 2016; reviewed by Stephen C. Harrison and Alasdair C. Steven). Published online before print October 31, 2016. We thank Zhiheng Yu, Chuan Hong, and Rick Huang (Janelia Farm) for assistance with cryo-EM data collection and motion correction; Hironori Sato for coordinates of the molecular dynamics model of full-length gp120; Sriram Subramaniam for gp120 coordinates from the KNH1144 SOSIP.681–17b complex; Alasdair McDowall and Songye Chen for training in cryo-EM techniques and data processing; Anthony West for performing alignment calculations; Jost Vielmetter and the Caltech Protein Expression Center for transfections and protein expression; and members of the P.J.B. and G.J.J. laboratories for helpful discussions and critical reading of the manuscript. This research was supported by the National Institutes of Health Grant 2 P50 GM082545-06 (to P.J.B.), National Institute Of Allergy and Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (to P.J.B.), and the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grant 1040753 (to P.J.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 National Institutes of Health. Author contributions: H.W. and P.J.B. designed research; H.W. and A.A.C. performed research; H.W., A.A.C., R.P.G., H.B.G., G.J.J., and P.J.B. analyzed data; and H.W., G.J.J., and P.J.B. wrote the paper. Reviewers: S.C.H., Children's Hospital Harvard Medical School and Howard Hughes Medical Institute; and A.C.S., National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH. The authors declare no conflict of interest. Data deposition: Data were deposited into the Protein Data Bank, www.pdb.org (PDB ID code 5THR) and The Electron Microscopy Data Bank, https://www.ebi.ac.uk/pdbe/emdb/ (entry no. EMD-8407). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1615939113/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHP50 GM082545-06
NIHP01 AI100148
Bill and Melinda Gates Foundation1040753
Gordon and Betty Moore FoundationUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Subject Keywords:cryo-EM; HIV-1 Env trimer; CD4; HIV-1 coreceptor; conformational change
PubMed Central ID:PMC5135367
Record Number:CaltechAUTHORS:20161101-072102928
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20161101-072102928
Official Citation:Haoqing Wang, Alexander A. Cohen, Rachel P. Galimidi, Harry B. Gristick, Grant J. Jensen, and Pamela J. Bjorkman Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop PNAS 2016 113 (46) E7151-E7158; published ahead of print October 31, 2016, doi:10.1073/pnas.1615939113
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:71644
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Nov 2016 17:14
Last Modified:09 Nov 2017 00:22

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