5TBE

Human p38alpha MAP Kinase in Complex with Dibenzosuberone Compound 2

5TBE の概要

• エントリーDOI: 10.2210/pdb5tbe/pdb
• 関連するPDBエントリー: 5TCO
• 分子名称: Mitogen-activated protein kinase 14, ~{N}-[2,4-bis(fluoranyl)-5-[[9-(2-morpholin-4-ylethylcarbamoyl)-11-oxidanylidene-5,6-dihydrodibenzo[1,2-~{d}:1',2'-~{f}][7]annulen-3-yl]amino]phenyl]thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: p38, kinase, inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41959.87

構造登録者

Buehrmann, M.,Rauh, D. (登録日: 2016-09-12, 公開日: 2017-04-19, 最終更新日: 2024-01-17)

主引用文献

Wentsch, H.K.,Walter, N.M.,Buhrmann, M.,Mayer-Wrangowski, S.,Rauh, D.,Zaman, G.J.R.,Willemsen-Seegers, N.,Buijsman, R.C.,Henning, M.,Dauch, D.,Zender, L.,Laufer, S.
Optimized Target Residence Time: Type I1/2 Inhibitors for p38 alpha MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine.
Angew. Chem. Int. Ed. Engl., 56:5363-5367, 2017

PubMed Abstract: Skepinone-L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP-competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I1/2 binders for p38α MAP kinase. Type I1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X-ray crystallography.

PubMed: 28397331
DOI: 10.1002/anie.201701185

実験手法

X-RAY DIFFRACTION (2.44 Å)