5KA6

HIV-1 gp41 variant Q552R and L555M resistance mutations

5KA6 の概要

• エントリーDOI: 10.2210/pdb5ka6/pdb
• 関連するPDBエントリー: 5KA5
• 分子名称: Transmembrane protein gp41 (2 entities in total)
• 機能のキーワード: hiv-1, membrane fusion, 5-helix, c-peptide, membrane protein
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 31898.78

構造登録者

Bhardwaj, A.,Khasnis, M.D.,Halkidis, K.,Root, M.J. (登録日: 2016-06-01, 公開日: 2016-12-14, 最終更新日: 2023-09-27)

主引用文献

Khasnis, M.D.,Halkidis, K.,Bhardwaj, A.,Root, M.J.
Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer.
PLoS Pathog., 12:e1006098-e1006098, 2016

PubMed Abstract: Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer-of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To characterize structural transformations into and through the PHI, we employed asymmetric Env trimers containing both high and low affinity binding sites for individual fusion inhibitors. Asymmetry was achieved using engineered Env heterotrimers composed of protomers deficient in either CD4- or chemokine receptor-binding. Linking receptor engagement to inhibitor affinity allowed us to assess conformational changes of individual Env protomers in the context of a functioning trimer. We found that the transition into the PHI could occur symmetrically or asymmetrically depending on the stoichiometry of CD4 binding. Sequential engagement of multiple CD4s promoted progressive exposure of individual fusion inhibitor binding sites in a CD4-dependent fashion. By contrast, engagement of only a single CD4 molecule led to a delayed, but symmetric, exposure of the gp41 trimer. This complex coupling between Env-CD4 interaction and gp41 exposure explained the multiphasic fusion-inhibitor titration observed for a mutant Env homotrimer with a naturally asymmetric gp41. Our results suggest that the spatial and temporal exposure of gp41 can proceed in a nonconcerted, asymmetric manner depending on the number of CD4s that engage the Env trimer. The findings have important implications for the mechanism of viral membrane fusion and the development of vaccine candidates designed to elicit neutralizing antibodies targeting gp41 in the PHI.

PubMed: 27992602
DOI: 10.1371/journal.ppat.1006098

実験手法

X-RAY DIFFRACTION (1.85 Å)