7KMA

Crystal structure of eif2Balpha with a ligand.

7KMA の概要

• エントリーDOI: 10.2210/pdb7kma/pdb
• 関連するPDBエントリー: 3ECS
• 分子名称: Translation initiation factor eIF-2B subunit alpha, 6-O-phosphono-alpha-D-mannopyranose, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: translation initiation factor eif-2b, translation factor activity, rna binding, translation regulator activity, nucleic acid binding, sugar binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 279444.92

構造登録者

Nocek, B.,Hao, Q.,Remarcik, C.,Stoll, V.,Wong, Y.,Sidrauski, C. (登録日: 2020-11-02, 公開日: 2021-07-21, 最終更新日: 2023-10-18)

主引用文献

Hao, Q.,Heo, J.M.,Nocek, B.P.,Hicks, K.G.,Stoll, V.S.,Remarcik, C.,Hackett, S.,LeBon, L.,Jain, R.,Eaton, D.,Rutter, J.,Wong, Y.L.,Sidrauski, C.
Sugar phosphate activation of the stress sensor eIF2B.
Nat Commun, 12:3440-3440, 2021

PubMed Abstract: The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. The eIF2B regulatory subcomplex is evolutionarily related to sugar-metabolizing enzymes, but the biological relevance of this relationship was unknown. To identify natural ligands that might regulate eIF2B, we conduct unbiased binding- and activity-based screens followed by structural studies. We find that sugar phosphates occupy the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2Bα ligand pocket that causes Vanishing White Matter disease fails to engage and is not stimulated by sugar phosphates. These data underscore the importance of allosteric metabolite modulation for proper eIF2B function. We propose that eIF2B evolved to couple nutrient status via sugar phosphate sensing with the rate of protein synthesis, one of the most energetically costly cellular processes.

PubMed: 34103529
DOI: 10.1038/s41467-021-23836-z

実験手法

X-RAY DIFFRACTION (2.7 Å)