3V6S

Discovery of potent and selective covalent inhibitors of JNK

3V6S の概要

• エントリーDOI: 10.2210/pdb3v6s/pdb
• 関連するPDBエントリー: 3V6R
• 分子名称: Mitogen-activated protein kinase 10, 3-{[4-(dimethylamino)butanoyl]amino}-N-(4-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide (3 entities in total)
• 機能のキーワード: kinase fold, apoptosis, map kinase, cys modification, jnk, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P53779
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85110.50

構造登録者

Park, H.,Laughlin, J.D.,LoGrasso, P.V. (登録日: 2011-12-20, 公開日: 2012-02-01, 最終更新日: 2024-11-27)

主引用文献

Zhang, T.,Inesta-Vaquera, F.,Niepel, M.,Zhang, J.,Ficarro, S.B.,Machleidt, T.,Xie, T.,Marto, J.A.,Kim, N.,Sim, T.,Laughlin, J.D.,Park, H.,LoGrasso, P.V.,Patricelli, M.,Nomanbhoy, T.K.,Sorger, P.K.,Alessi, D.R.,Gray, N.S.
Discovery of potent and selective covalent inhibitors of JNK.
Chem.Biol., 19:140-154, 2012

PubMed Abstract: The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3.

PubMed: 22284361
DOI: 10.1016/j.chembiol.2011.11.010

実験手法

X-RAY DIFFRACTION (2.97 Å)