This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
1q5k
From Proteopedia
|
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
