3ZSH

X-ray structure of p38alpha bound to SCIO-469

Summary for 3ZSH

• Entry DOI: 10.2210/pdb3zsh/pdb
• Related: 1A9U 1BL6 1BL7 1BMK 1DI9 1IAN 1KV1 1KV2 1M7Q 1OUK 1OUY 1OVE 1OZ1 1R39 1R3C 1W7H 1W82 1W83 1W84 1WBN 1WBO 1WBS 1WBT 1WBV 1WBW 1WFC 1YQJ 1ZYJ 1ZZ2 1ZZL 2BAJ 2BAK 2BAL 2BAQ 2I0H 2Y8O 2YIS 2YIW 2YIX 3ZS5 3ZSG 3ZSI
• Descriptor: MITOGEN-ACTIVATED PROTEIN KINASE 14, 2-(6-chloro-5-{[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide, octyl beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 42299.65

Authors

Azevedo, R.,van Zeeland, M.,Raaijmakers, H.,Kazemier, B.,Oubrie, A. (deposition date: 2011-06-28, release date: 2012-06-13, Last modification date: 2024-05-08)

Primary citation

Azevedo, R.,van Zeeland, M.,Raaijmakers, H.,Kazemier, B.,de Vlieg, J.,Oubrie, A.
X-ray structure of p38 alpha bound to TAK-715: comparison with three classic inhibitors.
Acta Crystallogr. D Biol. Crystallogr., 68:1041-1050, 2012

PubMed Abstract: The p38α mitogen-activated protein kinase regulates the synthesis of pro-inflammatory cytokines in response to stimulation by a diverse set of stress signals. Various different chemotypes and clinical candidates that inhibit p38α function have been reported over the years. In this publication, the novel structure of p38α cocrystallized with the clinical candidate TAK-715 is reported. Owing to the impact of crystallization conditions on the conformation of protein kinases (and in particular p38α), the structures of complexes of p38α with SB-203580, SCIO-469 and VX-745 have also been determined to enable in-depth comparison of ligand-induced protein conformations. The impact of experimental conditions on p38α-inhibitor complex structures, most importantly soaking versus cocrystallization, is discussed. Analysis of the structures and quantification of the protein-ligand interactions couples ligand-induced protein conformations to the number of interactions and to inhibitor selectivity against the human kinome. This shows that for the design of novel kinase inhibitors, selectivity is best obtained through maximization of the number of interactions throughout the ATP pocket and the exploitation of specific features in the active site.

PubMed: 22868770
DOI: 10.1107/S090744491201997X

Experimental method

X-RAY DIFFRACTION (2.05 Å)