1kv1
From Proteopedia
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p38 MAP Kinase in Complex with Inhibitor 1
Overview
The p38 MAP kinase plays a crucial role in regulating the production of, proinflammatory cytokines, such as tumor necrosis factor and, interleukin-1. Blocking this kinase may offer an effective therapy for, treating many inflammatory diseases. Here we report a new allosteric, binding site for a diaryl urea class of highly potent and selective, inhibitors against human p38 MAP kinase. The formation of this binding, site requires a large conformational change not observed previously for, any of the protein Ser/Thr kinases. This change is in the highly conserved, Asp-Phe-Gly motif within the active site of the kinase. Solution studies, demonstrate that this class of compounds has slow binding kinetics, consistent with the requirement for conformational change. Improving, interactions in this allosteric pocket, as well as establishing binding, interactions in the ATP pocket, enhanced the affinity of the inhibitors by, 12,000-fold. One of the most potent compounds in this series, BIRB 796, has picomolar affinity for the kinase and low nanomolar inhibitory, activity in cell culture.
About this Structure
1KV1 is a Single protein structure of sequence from Homo sapiens with BMU as ligand. Full crystallographic information is available from OCA.
Reference
Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site., Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J, Nat Struct Biol. 2002 Apr;9(4):268-72. PMID:11896401
Page seeded by OCA on Mon Nov 12 17:54:59 2007
