6CAJ

Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens

6CAJ の概要

• エントリーDOI: 10.2210/pdb6caj/pdb
• 関連するPDBエントリー: 6caj
• EMDBエントリー: 7442 7443 7444
• 分子名称: Translation initiation factor eIF-2B subunit epsilon, Translation initiation factor eIF-2B subunit gamma, Translation initiation factor eIF-2B subunit alpha, ... (6 entities in total)
• 機能のキーワード: guanine nucleotide exchange factor, translation initiation, isrib-bound, decameric complex, 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: 526770.76

構造登録者

Tsai, J.C.,Miller-Vedam, L.E.,Anand, A.A.,Jaishankar, P.,Nguyen, H.C.,Renslo, A.R.,Frost, A.,Walter, P. (登録日: 2018-01-31, 公開日: 2018-04-11, 最終更新日: 2019-11-20)

主引用文献

Tsai, J.C.,Miller-Vedam, L.E.,Anand, A.A.,Jaishankar, P.,Nguyen, H.C.,Renslo, A.R.,Frost, A.,Walter, P.
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.
Science, 359:-, 2018

PubMed Abstract: Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.

PubMed: 29599213
DOI: 10.1126/science.aaq0939

実験手法

ELECTRON MICROSCOPY (2.8 Å)