6EKD

Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor

6EKD の概要

• エントリーDOI: 10.2210/pdb6ekd/pdb
• 分子名称: Mitogen-activated protein kinase 10, BETA-MERCAPTOETHANOL, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: protein kinase activity map kinase activity atp binding protein phosphorylation, 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: 42782.55

構造登録者

Macedo, J.T.,Stehle, T.,Blaum, B.S. (登録日: 2017-09-26, 公開日: 2018-08-08, 最終更新日: 2024-01-17)

主引用文献

Ansideri, F.,Macedo, J.T.,Eitel, M.,El-Gokha, A.,Zinad, D.S.,Scarpellini, C.,Kudolo, M.,Schollmeyer, D.,Boeckler, F.M.,Blaum, B.S.,Laufer, S.A.,Koch, P.
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38 alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.
ACS Omega, 3:7809-7831, 2018

PubMed Abstract: Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38α MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group. Furthermore, additional structural modifications permitted to explore structure-activity relationships. The most potent inhibitor 4-(4-methyl-2-(methylthio)-1-imidazol-5-yl)--(4-morpholinophenyl)pyridin-2-amine showed an IC value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.

PubMed: 30087925
DOI: 10.1021/acsomega.8b00668

実験手法

X-RAY DIFFRACTION (2.1 Å)