2023-11-22 ã«ãªãã©ã«ãã¢å·¥ç§å€§åŠ(Caltech)
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- https://www.caltech.edu/about/news/imaging-breakthroughs-provide-insight-into-the-dynamic-architectures-of-hiv-proteins
- https://www.nature.com/articles/s41586-023-06639-8
CD4ã«çµåããHIV-1 Envãããäžéäœã®äžéæ§é Intermediate conformations of CD4-bound HIV-1 Env heterotrimers
Kim-Marie A. Dam,Chengcheng Fan,Zhi Yang & Pamela J. Bjorkman
Nature Published:22 November 2023
DOI:https://doi.org/10.1038/s41586-023-06639-8
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 closed, prefusion conformation with closely associated gp120s and coreceptor binding sites on gp120 V3 hidden by V1V2 loops1,2,3,4 and in fully saturated CD4-bound open Env conformations with changes including outwardly rotated gp120s and displaced V1V2 loops3,4,5,6,7,8,9. 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 state10 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. 11), validating their physiological relevance. Together, these results illuminate intermediate conformations of HIV-1 Env and illustrate its structural plasticity.
