3NPC

Crystal structure of JNK2 complexed with BIRB796

3NPC の概要

• エントリーDOI: 10.2210/pdb3npc/pdb
• 分子名称: Mitogen-activated protein kinase 9, 1-(5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL)-3-[4-(2-MORPHOLIN-4-YL-ETHOXY)-NAPHTHALEN-1-YL]-UREA (3 entities in total)
• 機能のキーワード: dfg-out, protein kinase, transferase, atp binding, type ii kinase inhibitor, 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: 2
• 化学式量合計: 84847.97

構造登録者

Kuglstatter, A.,Ghate, M. (登録日: 2010-06-28, 公開日: 2010-08-11, 最終更新日: 2023-09-06)

主引用文献

Kuglstatter, A.,Ghate, M.,Tsing, S.,Villasenor, A.G.,Shaw, D.,Barnett, J.W.,Browner, M.F.
X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: Insights into the rational design of DFG-out binding MAP kinase inhibitors.
Bioorg.Med.Chem.Lett., 20:5217-5220, 2010

PubMed Abstract: JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential.

PubMed: 20655210
DOI: 10.1016/j.bmcl.2010.06.157

実験手法

X-RAY DIFFRACTION (2.35 Å)