6X5B

Symmetric model of CD4- and 17-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52

6X5B の概要

• エントリーDOI: 10.2210/pdb6x5b/pdb
• EMDBエントリー: 22048
• 分子名称: Envelope glycoprotein gp120, Envelope glycoprotein gp41, 17b Fab light chain, ... (9 entities in total)
• 機能のキーワード: hiv-1, env, cd4, receptor-bound state, small molecule, viral protein, viral protein-immune system complex
• 由来する生物種: Human immunodeficiency virus 1 (HIV-1); 詳細
• タンパク質・核酸の鎖数: 15
• 化学式量合計: 452528.23

構造登録者

Ozorowski, G.,Torres, J.L.,Ward, A.B. (登録日: 2020-05-25, 公開日: 2020-10-21, 最終更新日: 2024-11-20)

主引用文献

Ozorowski, G.,Torres, J.L.,Santos-Martins, D.,Forli, S.,Ward, A.B.
A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.
Cell Rep, 33:108428-108428, 2020

PubMed Abstract: Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.

PubMed: 33238117
DOI: 10.1016/j.celrep.2020.108428

実験手法

ELECTRON MICROSCOPY (3.6 Å)