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

Author

Listed:
  • Claudia A. Jette

    (California Institute of Technology)

  • Christopher O. Barnes

    (California Institute of Technology)

  • Sharon M. Kirk

    (University of Pennsylvania)

  • Bruno Melillo

    (University of Pennsylvania)

  • Amos B. Smith

    (University of Pennsylvania)

  • Pamela J. Bjorkman

    (California Institute of Technology)

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.

Suggested Citation

  • Claudia A. Jette & Christopher O. Barnes & Sharon M. Kirk & Bruno Melillo & Amos B. Smith & Pamela J. Bjorkman, 2021. "Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21816-x
    DOI: 10.1038/s41467-021-21816-x
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    Cited by:

    1. Durgadevi Parthasarathy & Karunakar Reddy Pothula & Sneha Ratnapriya & Héctor Cervera Benet & Ruth Parsons & Xiao Huang & Salam Sammour & Katarzyna Janowska & Miranda Harris & Joseph Sodroski & Priyam, 2024. "Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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