8TQZ

Eukaryotic translation initiation factor 2B with a mutation (L516A) in the delta subunit

8TQZ の概要

• エントリーDOI: 10.2210/pdb8tqz/pdb
• EMDBエントリー: 41566
• 分子名称: Translation initiation factor eIF-2B subunit alpha, Translation initiation factor eIF-2B subunit epsilon, Translation initiation factor eIF-2B subunit beta, ... (5 entities in total)
• 機能のキーワード: protein translation, eif2b, integrated stress response, 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: 530173.34

構造登録者

Wang, L.,Lawrence, R.,Sangwan, S.,Anand, A.,Shoemaker, S.,Deal, A.,Marqusee, S.,Watler, P. (登録日: 2023-08-08, 公開日: 2023-12-06, 最終更新日: 2024-04-10)

主引用文献

Lawrence, R.E.,Shoemaker, S.R.,Deal, A.,Sangwan, S.,Anand, A.A.,Wang, L.,Marqusee, S.,Walter, P.
A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.
Nat.Chem.Biol., 20:422-431, 2024

PubMed Abstract: The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.

PubMed: 37945896
DOI: 10.1038/s41589-023-01453-9

実験手法

ELECTRON MICROSCOPY (2.9 Å)