3UVP

Human p38 MAP Kinase in Complex with a Benzamide Substituted Benzosuberone

3UVP の概要

• エントリーDOI: 10.2210/pdb3uvp/pdb
• 関連するPDBエントリー: 3QUD 3QUE 3UVQ 3UVR 3UVS
• 分子名称: Mitogen-activated protein kinase 14, N-{2-fluoro-5-[(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino]phenyl}benzamide, octyl beta-D-glucopyranoside, ... (4 entities in total)
• 機能のキーワード: protein kinase, selective p38 inhibitor, sar, benzosuberon derivative, 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: 42242.23

構造登録者

Mayer-Wrangowski, S.C.,Richters, A.,Gruetter, C.,Rauh, D. (登録日: 2011-11-30, 公開日: 2012-11-07, 最終更新日: 2023-11-08)

主引用文献

Martz, K.E.,Dorn, A.,Baur, B.,Schattel, V.,Goettert, M.I.,Mayer-Wrangowski, S.C.,Rauh, D.,Laufer, S.A.
Targeting the Hinge Glycine Flip and the Activation Loop: Novel Approach to Potent p38 alpha Inhibitors.
J.Med.Chem., 55:7862-7874, 2012

PubMed Abstract: The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.

PubMed: 22897496
DOI: 10.1021/jm300951u

実験手法

X-RAY DIFFRACTION (2.4 Å)