2baj: Difference between revisions
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[[Image:2baj.gif|left|200px]] | [[Image:2baj.gif|left|200px]] | ||
'''p38alpha bound to pyrazolourea''' | {{Structure | ||
|PDB= 2baj |SIZE=350|CAPTION= <scene name='initialview01'>2baj</scene>, resolution 2.25Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=1PP:(S)-{[(3R)-5-TERT-BUTYL-2-PHENYL-2,3-DIHYDRO-1H-PYRAZOL-3-YL]AMINO}[(2,3-DICHLOROPHENYL)AMINO]METHANOL'>1PP</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] | |||
|GENE= MAPK14, CSBP, CSBP1, CSBP2, MXI2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''p38alpha bound to pyrazolourea''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2BAJ is a [ | 2BAJ 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=2BAJ OCA]. | ||
==Reference== | ==Reference== | ||
Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase., Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WH, Biochemistry. 2005 Dec 20;44(50):16475-90. PMID:[http:// | Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase., Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WH, Biochemistry. 2005 Dec 20;44(50):16475-90. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16342939 16342939] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
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[[Category: mitogen activated protein kinase]] | [[Category: mitogen activated protein kinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:59:23 2008'' | ||
Revision as of 16:59, 20 March 2008
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| , resolution 2.25Å | |||||||
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| Ligands: | |||||||
| Gene: | MAPK14, CSBP, CSBP1, CSBP2, MXI2 (Homo sapiens) | ||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
p38alpha bound to pyrazolourea
OverviewOverview
Inhibition of p38alpha MAP kinase is a potential approach for the treatment of inflammatory disorders. MKK6-dependent phosphorylation on the activation loop of p38alpha increases its catalytic activity and affinity for ATP. An inhibitor, BIRB796, binds at a site used by the purine moiety of ATP and extends into a "selectivity pocket", which is not used by ATP. It displaces the Asp168-Phe169-Gly170 motif at the start of the activation loop, promoting a "DFG-out" conformation. Some other inhibitors bind only in the purine site, with p38alpha remaining in a "DFG-in" conformation. We now demonstrate that selectivity pocket compounds prevent MKK6-dependent activation of p38alpha in addition to inhibiting catalysis by activated p38alpha. Inhibitors using only the purine site do not prevent MKK6-dependent activation. We present kinetic analyses of seven inhibitors, whose crystal structures as complexes with p38alpha have been determined. This work includes four new crystal structures and a novel assay to measure K(d) for nonactivated p38alpha. Selectivity pocket compounds associate with p38alpha over 30-fold more slowly than purine site compounds, apparently due to low abundance of the DFG-out conformation. At concentrations that inhibit cellular production of an inflammatory cytokine, TNFalpha, selectivity pocket compounds decrease levels of phosphorylated p38alpha and beta. Stabilization of a DFG-out conformation appears to interfere with recognition of p38alpha as a substrate by MKK6. ATP competes less effectively for prevention of activation than for inhibition of catalysis. By binding to a different conformation of the enzyme, compounds that prevent activation offer an alternative approach to modulation of p38alpha.
About this StructureAbout this Structure
2BAJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase., Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WH, Biochemistry. 2005 Dec 20;44(50):16475-90. PMID:16342939
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