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bioRxiv · 10.1101/2020.08.21.261974

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

Jette, C. A.·Barnes, C. O.·Kirk, S. M.·Melillo, B.·Smith, A. B.·Bjorkman, P. J.
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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 CD4s 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[A] and 3.9[A] 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.

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Jette, C. A., Barnes, C. O., Kirk, S. M., Melillo, B., Smith, A. B., Bjorkman, P. J.. 2020-08-22. Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics M48U1 and BNM-III-170 adopt a CD4-bound open conformation. https://doi.org/10.1101/2020.08.21.261974

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