1q5k | pdb_00001q5k
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
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- 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
