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Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics M48U1 and BNM-III-170 adopt a CD4-bound open conformation

Jette, Claudia A. and Barnes, Christopher O. and Kirk, Sharon M. and Melillo, Bruno and Smith, Amos B., III and Bjorkman, Pamela J. (2020) Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics M48U1 and BNM-III-170 adopt a CD4-bound open conformation. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200824-121127298

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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 3.7Å and 3.9Å 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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.08.21.261974DOIDiscussion Paper
ORCID:
AuthorORCID
Jette, Claudia A.0000-0002-5085-8027
Barnes, Christopher O.0000-0003-2754-5951
Melillo, Bruno0000-0002-9708-5287
Smith, Amos B., III0000-0002-1712-8567
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Posted August 22, 2020. 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 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. 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 refinemnet, 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.
Funders:
Funding AgencyGrant Number
NIH2 P50 AI150464
NIHP01 AI100148
NIHAI50471
NIHGM56550
NIHU24GM129547
Department of Energy (DOE)UNSPECIFIED
Record Number:CaltechAUTHORS:20200824-121127298
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200824-121127298
Official Citation:Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics M48U1 and BNM-III-170 adopt a CD4-bound open conformation. Claudia A. Jette, Christopher O. Barnes, Sharon M. Kirk, Bruno Melillo, Amos B. Smith III, Pamela J. Bjorkman. bioRxiv 2020.08.21.261974; doi: https://doi.org/10.1101/2020.08.21.261974
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105071
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Aug 2020 20:15
Last Modified:24 Aug 2020 20:15

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