1kv1: Difference between revisions
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[[Image:1kv1.gif|left|200px]] | [[Image:1kv1.gif|left|200px]] | ||
'''p38 MAP Kinase in Complex with Inhibitor 1''' | {{Structure | ||
|PDB= 1kv1 |SIZE=350|CAPTION= <scene name='initialview01'>1kv1</scene>, resolution 2.5Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=BMU:1-(5-TERT-BUTYL-2-METHYL-2H-PYRAZOL-3-YL)-3-(4-CHLORO-PHENYL)-UREA'>BMU</scene> | |||
|ACTIVITY= | |||
|GENE= | |||
}} | |||
'''p38 MAP Kinase in Complex with Inhibitor 1''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1KV1 is a [ | 1KV1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KV1 OCA]. | ||
==Reference== | ==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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11896401 11896401] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
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Revision as of 13:22, 20 March 2008
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p38 MAP Kinase in Complex with Inhibitor 1
OverviewOverview
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 StructureAbout this Structure
1KV1 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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