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

Claudia A. Jette, Christopher O. Barnes, Sharon M. Kirk, Bruno Melillo, Amos B. Smith and Pamela J. Bjorkman ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21816-x

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