1q5k
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(New page: 200px<br /> <applet load="1q5k" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q5k, resolution 1.94Å" /> '''crystal structure o...)
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Revision as of 16:44, 12 November 2007
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crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor
Overview
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 > 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.
About this Structure
1Q5K is a Single protein structure of sequence from Homo sapiens with TMU as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 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
Page seeded by OCA on Mon Nov 12 18:50:40 2007
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Single protein | Avila, J. | Berg, S. | Bhat, R. | Borgegard, T. | Diaz-Mido, J. | Gimenez-Cassina, A. | Hellberg, S. | Hernandez, F. | Jerning, E. | Lucas, J.J. | Markgren, P.O. | Nilsson, Y. | Nylof, M. | Ormo, M. | Radesater, A.C. | Xue, Y. | TMU | Kinase-inhibitor complex
