6U06

Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

6U06 の概要

• エントリーDOI: 10.2210/pdb6u06/pdb
• 分子名称: Eukaryotic translation initiation factor 4E, 3-{[(4-cyanophenyl)methyl](1-oxo-1,2-dihydroisoquinolin-7-yl)sulfamoyl}benzene-1-sulfonyl fluoride (3 entities in total)
• 機能のキーワード: cap-binding site, anti-neoplastic, inhibitor, translation initiation blocking, translation, translation-inhibitor complex
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 90570.53

構造登録者

Wan, X.B.,Shoichet, B.K.,Taunton, J. (登録日: 2019-08-13, 公開日: 2019-10-16, 最終更新日: 2024-10-23)

主引用文献

Wan, X.,Yang, T.,Cuesta, A.,Pang, X.,Balius, T.E.,Irwin, J.J.,Shoichet, B.K.,Taunton, J.
Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking.
J.Am.Chem.Soc., 142:4960-4964, 2020

PubMed Abstract: Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride to , which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.

PubMed: 32105459
DOI: 10.1021/jacs.9b10377

実験手法

X-RAY DIFFRACTION (1.96 Å)