1q5k: Difference between revisions

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[[Image:1q5k.gif|left|200px]]
{{Seed}}
[[Image:1q5k.png|left|200px]]


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{{STRUCTURE_1q5k|  PDB=1q5k  |  SCENE=  }}  
{{STRUCTURE_1q5k|  PDB=1q5k  |  SCENE=  }}  


'''crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor'''
===crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor===




==Overview==
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Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 &gt; 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
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{{ABSTRACT_PUBMED_12928438}}


==About this Structure==
==About this Structure==
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[[Category: Xue, Y.]]
[[Category: Xue, Y.]]
[[Category: Kinase-inhibitor complex]]
[[Category: Kinase-inhibitor complex]]
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Revision as of 12:50, 27 July 2008

File:1q5k.png

Template:STRUCTURE 1q5k

crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor

Template:ABSTRACT PUBMED 12928438

About this Structure

1Q5K is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418., Bhat R, Xue Y, Berg S, Hellberg S, Ormo M, Nilsson Y, Radesater AC, Jerning E, Markgren PO, Borgegard T, Nylof M, Gimenez-Cassina A, Hernandez F, Lucas JJ, Diaz-Nido J, Avila J, J Biol Chem. 2003 Nov 14;278(46):45937-45. Epub 2003 Aug 19. PMID:12928438

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