5TCO

Human p38 MAP Kinase in Complex with Dibenzosuberone Compound 1

Summary for 5TCO

• Entry DOI: 10.2210/pdb5tco/pdb
• Related: 5TBE
• Descriptor: Mitogen-activated protein kinase 14, 3-[(3-benzamido-4-fluoranyl-phenyl)amino]-~{N}-(2-morpholin-4-ylethyl)-11-oxidanylidene-5,6-dihydrodibenzo[1,2-~{d}:1',2'-~{f}][7]annulene-9-carboxamide, octyl beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: inhibitor, dibenzosuberone, human p38 map kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42446.45

Authors

Mayer-Wrangowski, S.C.,Rauh, D. (deposition date: 2016-09-15, release date: 2017-04-19, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)