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| Title | Intermediate conformations of CD4-bound HIV-1 Env heterotrimers. |
|---|---|
| Journal, issue, pages | Nature, Vol. 623, Issue 7989, Page 1017-1025, Year 2023 |
| Publish date | Nov 22, 2023 |
 Authors | Kim-Marie A Dam / Chengcheng Fan / Zhi Yang / Pamela J Bjorkman /  |
| PubMed Abstract | HIV-1 envelope (Env) exhibits distinct conformational changes in response to host receptor (CD4) engagement. Env, a trimer of gp120 and gp41 heterodimers, has been structurally characterized in a ...HIV-1 envelope (Env) exhibits distinct conformational changes in response to host receptor (CD4) engagement. Env, a trimer of gp120 and gp41 heterodimers, has been structurally characterized in a closed, prefusion conformation with closely associated gp120s and coreceptor binding sites on gp120 V3 hidden by V1V2 loops and in fully saturated CD4-bound open Env conformations with changes including outwardly rotated gp120s and displaced V1V2 loops. To investigate changes resulting from substoichiometric CD4 binding, we solved single-particle cryo-electron microscopy (cryo-EM) structures of soluble, native-like heterotrimeric Envs bound to one or two CD4 molecules. Most of the Env trimers bound to one CD4 adopted the closed, prefusion Env state, with a minority exhibiting a heterogeneous partially open Env conformation. When bound to two CD4s, the CD4-bound gp120s exhibited an open Env conformation including a four-stranded gp120 bridging sheet and displaced gp120 V1V2 loops that expose the coreceptor sites on V3. The third gp120 adopted an intermediate, occluded-open state that showed gp120 outward rotation but maintained the prefusion three-stranded gp120 bridging sheet with only partial V1V2 displacement and V3 exposure. We conclude that most of the engagements with one CD4 molecule were insufficient to stimulate CD4-induced conformational changes, whereas binding two CD4 molecules led to Env opening in CD4-bound protomers only. The substoichiometric CD4-bound soluble Env heterotrimer structures resembled counterparts derived from a cryo-electron tomography study of complexes between virion-bound Envs and membrane-anchored CD4 (ref. ), validating their physiological relevance. Together, these results illuminate intermediate conformations of HIV-1 Env and illustrate its structural plasticity. |
 External links | Nature / PubMed:37993719 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 - 6.4 Å |
| Structure data | EMDB-29579, PDB-8fyi: EMDB-29580, PDB-8fyj:  EMDB-29581: HIV-1 BG505 SOSIP-HT2 in complex with CD4 (class II)  EMDB-29582: HIV-1 BG505 SOSIP-HT2 in complex with CD4 (class III)  EMDB-29583: HIV-1 BG505 SOSIP-HT1 in complex with CD4 and 17b Fab  EMDB-29584: HIV-1 BG505 SOSIP-HT2 in complex with CD4 and 17b Fab  EMDB-29601: HIV-1 B41 SOSIP-HT2 in complex with CD4  EMDB-40437: Structure of HIV-1 BG505 SOSIP-HT1 in complex with CD4 (class II)  EMDB-40438: Structure of HIV-1 BG505 SOSIP-HT1 (class III) |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords | Viral protein/IMMUNE SYSTEM / Viral protein / HIV / IMMUNE SYSTEM / Viral protein-IMMUNE SYSTEM complex / HIV-1 |
human immunodeficiency virus 1
homo sapiens (human)