7ORE

Crystal structure of JNK3 in complex with light-activated covalent inhibitor MR-II-249 with both non-covalent and covalent binding modes (compound 4)

7ORE の概要

• エントリーDOI: 10.2210/pdb7ore/pdb
• 分子名称: Mitogen-activated protein kinase 10, 4-(dimethylamino)-N-[(5Z)-9-[[4-[5-(4-fluorophenyl)-3-methyl-2-methylsulfanyl-imidazol-4-yl]pyridin-2-yl]amino]-11,12-dihydrobenzo[c][1,2]benzodiazocin-2-yl]butanamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: kinase, mapk, mapk10, light activation, covalent inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44002.95

構造登録者

Chaikuad, A.,Reynders, M.,Trauner, D.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2021-06-05, 公開日: 2021-07-21, 最終更新日: 2025-10-01)

主引用文献

Reynders, M.,Chaikuad, A.,Berger, B.T.,Bauer, K.,Koch, P.,Laufer, S.,Knapp, S.,Trauner, D.
Controlling the Covalent Reactivity of a Kinase Inhibitor with Light.
Angew.Chem.Int.Ed.Engl., 60:20178-20183, 2021

PubMed Abstract: Covalent kinase inhibitors account for some of the most successful drugs that have recently entered the clinic and many others are in preclinical development. A common strategy is to target cysteines in the vicinity of the ATP binding site using an acrylamide electrophile. To increase the tissue selectivity of kinase inhibitors, it could be advantageous to control the reactivity of these electrophiles with light. Here, we introduce covalent inhibitors of the kinase JNK3 that function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, are poor non-covalent inhibitors in the dark, and become effective covalent inhibitors after irradiation with visible light. Our proposed mode of action is supported by X-ray structures that explain why these compounds are unreactive in the dark and undergo proximity-based covalent attachment following exposure to light.

PubMed: 34081840
DOI: 10.1002/anie.202103767

実験手法

X-RAY DIFFRACTION (2.18 Å)