7D46

eIF2B apo

7D46 の概要

• エントリーDOI: 10.2210/pdb7d46/pdb
• EMDBエントリー: 30571
• 分子名称: Translation initiation factor eIF-2B subunit alpha, Translation initiation factor eIF-2B subunit beta, Translation initiation factor eIF-2B subunit gamma, ... (5 entities in total)
• 機能のキーワード: complex, translational control, translation
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 522409.40

構造登録者

Kashiwagi, K.,Ito, T. (登録日: 2020-09-22, 公開日: 2020-12-09, 最終更新日: 2025-07-02)

主引用文献

Zyryanova, A.F.,Kashiwagi, K.,Rato, C.,Harding, H.P.,Crespillo-Casado, A.,Perera, L.A.,Sakamoto, A.,Nishimoto, M.,Yonemochi, M.,Shirouzu, M.,Ito, T.,Ron, D.
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.
Mol.Cell, 81:88-, 2021

PubMed Abstract: The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

PubMed: 33220178
DOI: 10.1016/j.molcel.2020.10.031

実験手法

ELECTRON MICROSCOPY (4 Å)