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,Sharon M Kirk,Christopher O Barnes,Pamela J Bjorkman,Amos B Smith,Bruno Melillo

doi:10.1038/s41467-021-21816-x

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.

Highlights

Human immunodeficiency virus-1 (HIV-1), the causative agent of Acquired Immunodeficiency Syndrome (AIDS), impacts millions of people
Of note, binding of 17b was lower for BG505 incubated with BNM-III-170 (Supplementary Fig. 1c), suggesting that some of the BG505 Envs were in a conformation not accessible for binding to 17b. 21c IgG bound to BG505 plus soluble CD4 (sCD4) but did not bind to BG505 incubated with BNM-III-170 or M48U1 (Supplementary Fig. 1b–d), consistent with the requirement of the epitope of this antibody spanning CD4 and gp12032
Using single-particle cryo-EM, we found that two CD4 mimetic (CD4m) compounds, BNM-III-170 and M48U1, bound to the native-like BG505 Env trimer resulted in open trimer structures similar to sCD4-bound structures, both in terms of inter-subunit gp[120] rotation and displacement and in terms of intra-subunit conformational changes

Summary

Introduction

Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. X-ray and cryo-EM structures of native-like soluble HIV-1 Env trimers (SOSIPs8) have defined a closed, prefusion state in which the V1V2 loops at the trimer apex shield the co-receptor binding site on the V3 region[9], and a CD4-bound open state in which the gp[120] subunits rotate outwards from the trimer axis, the V1V2 loops are displaced to the sides of the trimer, and the V3 loops are exposed[3,4,5,6]. A key interaction for exposure of the co-receptor binding site upon CD4 binding is the insertion of CD4 residue Phe43CD4 into a conserved, 150Å2 hydrophobic cavity at the junction between the gp[120] inner domain, outer domain, and bridging sheet[10] This interaction was first observed in crystal structures of monomeric gp[120] cores complexed with CD410, which adopt a hallmark feature of CD4-bound Env trimers in the presence or absence of CD4: a 4-stranded anti-parallel β-sheet comprising β-strands β20, β21, β2, and β311. The Env trimer is kept closed by allosterically preventing CD4 binding by separating the bridging sheet and the inner domain of gp12020,21

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Results

Conclusion