Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation
Abstract
Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4's Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7 Å and 3.9 Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket.
Additional Information
© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 14 August 2020; Accepted 11 February 2021; Published 29 March 2021. Cryo-EM was performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech with assistance from directors A. Malyutin and S. Chen. We thank J. Vielmetter and the Beckman Institute Protein Expression Center at Caltech for protein production, J.E. Robinson (Tulane University) for the JR-52 antibody, John Moore (Weill Cornell Medical College) for the BG505 stable cell line. This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant INV-002143 (P.J.B.) and the National Institute of Allergy and Infectious Diseases (NIAID) Grant numbers 2 P50 AI150464 and HIVRAD P01 AI100148 (P.J.B.) and AI50471 and GM56550 (A.B.S.). A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. Data availability: The structural coordinates were deposited into the Worldwide Protein Data Bank (wwPDB) with accession codes 7LO6 [https://doi.org/10.2210/pdb7LO6/pdb] (BNM-III-170-BG505-17b) and 7LOK [https://doi.org/10.2210/pdb7LOK/pdb] (M48U1-BG505-17b). EM density maps were deposited into EMDB with accession numbers EMD-23462 (BNM-III-170-BG505-17b) and EMD-23465 (M48U1-BG505-17b). Other data are available upon reasonable request. Author Contributions: C.A.J. designed experiments, purified proteins, assembled protein, and cryo-EM samples, collected cryo-EM data, processed cryo-EM data, performed model building, and refinement, analyzed data, performed ELISA experiments, and wrote the manuscript. C.O.B. designed experiments, purified proteins, collected cryo-EM data, assisted in data processing, assisted in model building and refinement, and assisted in ELISA experiments. S.M.K. and B.M. developed and synthesized BNM-III-170. A.B.S. supervised and guided BNM-III-170 development. P.J.B. supervised and guided the project and wrote the manuscript. The authors declare no competing interests. Peer review information: Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.Attached Files
Published - s41467-021-21816-x.pdf
Submitted - 2020.08.21.261974v1.full.pdf
Supplemental Material - 41467_2021_21816_MOESM1_ESM.pdf
Supplemental Material - 41467_2021_21816_MOESM2_ESM.pdf
Supplemental Material - 41467_2021_21816_MOESM3_ESM.pdf
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Additional details
- Alternative title
- Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation
- PMCID
- PMC8007822
- Eprint ID
- 105071
- Resolver ID
- CaltechAUTHORS:20200824-121127298
- INV-002143
- Bill and Melinda Gates Foundation
- 2 P50 AI150464
- NIH
- P01 AI100148
- NIH
- AI50471
- NIH
- GM56550
- NIH
- U24GM129547
- NIH
- Department of Energy (DOE)
- Created
-
2020-08-24Created from EPrint's datestamp field
- Updated
-
2021-04-21Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering