1Q5K

crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor

Summary for 1Q5K

• Entry DOI: 10.2210/pdb1q5k/pdb
• Descriptor: Glycogen synthase kinase-3 beta, N-(4-METHOXYBENZYL)-N'-(5-NITRO-1,3-THIAZOL-2-YL)UREA (3 entities in total)
• Functional Keywords: kinase-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 92845.41

Authors

Bhat, R.,Xue, Y.,Berg, S.,Hellberg, S.,Ormo, M.,Nilsson, Y.,Radesater, A.C.,Jerning, E.,Markgren, P.O.,Borgegard, T.,Nylof, M.,Gimenez-Cassina, A.,Hernandez, F.,Lucas, J.J.,Diaz-Mido, J.,Avila, J. (deposition date: 2003-08-08, release date: 2004-08-10, Last modification date: 2024-02-14)

Primary citation

Bhat, R.,Xue, Y.,Berg, S.,Hellberg, S.,Ormo, M.,Nilsson, Y.,Radesater, A.C.,Jerning, E.,Markgren, P.O.,Borgegard, T.,Nylof, M.,Gimenez-Cassina, A.,Hernandez, F.,Lucas, J.J.,Diaz-Nido, J.,Avila, J.
Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.
J.Biol.Chem., 278:45937-45945, 2003

PubMed Abstract: 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.

PubMed: 12928438
DOI: 10.1074/jbc.M306268200

Experimental method

X-RAY DIFFRACTION (1.94 Å)