4W4X

JNK2/3 in complex with 3-(4-{[(4-fluorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-N-(2-methylpyridin-4-yl)benzamide

4W4X の概要

• エントリーDOI: 10.2210/pdb4w4x/pdb
• 関連するPDBエントリー: 4W4V 4W4W 4W4Y
• 分子名称: c-jun NH2-terminal kinase 3, 3-(4-{[(4-fluorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-N-(2-methylpyridin-4-yl)benzamide (3 entities in total)
• 機能のキーワード: jnk, map kinase, isoform selective, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 42692.38

構造登録者

Park, H.,Iqbal, S.,Hernandez, P.,Mora, R.,Zheng, K.,Feng, Y.,LoGrasso, P. (登録日: 2014-08-15, 公開日: 2015-02-11, 最終更新日: 2023-12-27)

主引用文献

Park, H.,Iqbal, S.,Hernandez, P.,Mora, R.,Zheng, K.,Feng, Y.,LoGrasso, P.
Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles.
Sci Rep, 5:8047-8047, 2015

PubMed Abstract: Three JNK isoforms, JNK1, JNK2, and JNK3 have been reported and unique biological function has been ascribed to each. It is unknown if selective inhibition of these isoforms would confer therapeutic or safety benefit. To probe JNK isoform function we designed JNK2/3 inhibitors that have >30-fold selectivity over JNK1. Utilizing site-directed mutagenesis and x-ray crystallography we identified L144 in JNK3 as a key residue for selectivity. To test whether JNK2/3 selective inhibitors protect human dopaminergic neurons against neurotoxin-induced mitochondrial dysfunction, we monitored reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP). The results showed that JNK2/3 selective inhibitors protected against 6-hydroxydopamine-induced ROS generation and MMP depolarization. These results suggest that it was possible to develop JNK2/3 selective inhibitors and that residues in hydrophobic pocket I were responsible for selectivity. Moreover, the findings also suggest that inhibition of JNK2/3 likely contributed to protecting mitochondrial function and prevented ultimate cell death.

PubMed: 25623238
DOI: 10.1038/srep08047

実験手法

X-RAY DIFFRACTION (2.65 Å)