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Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418
Open accessAbstract
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.
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Self-citationTau protein kinases: Involvement in Alzheimer's disease
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Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis
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Metadata
- Authors
- Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormö, M., Nilsson, Y., Radesäter, A.-C., Jerning, E., Markgren, P.-O., Borgegård, T., Nylöf, M., Giménez-Cassina, A., Hernández, F., Lucas, J. J., Díaz-Nido, J., & Avila, J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 46
- Pages
- 45937-45945
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2161182074
- Cited by
- 552
- References
- 9
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormö, M., Nilsson, Y., Radesäter, A.-C., Jerning, E., Markgren, P.-O., Borgegård, T., Nylöf, M., Giménez-Cassina, A., Hernández, F., Lucas, J. J., Díaz-Nido, J., & Avila, J. (2003). Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m306268200
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