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Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2004
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2004.
-
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 (K i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 μM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3β 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 β-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.<br />Supported by grants from the Comunidad de Madrid, the Fundacion “La Caixa,” the Lilly Foundation, the Spanish Comision Interministerial de Ciencia y Tecnologia, and an institutional grant from the Fundacion Ramon Areces.
- Subjects :
- Models, Molecular
animal structures
Cell Survival
Electrons
tau Proteins
macromolecular substances
Mitogen-activated protein kinase kinase
Biology
Crystallography, X-Ray
Biochemistry
MAP2K7
Glycogen Synthase Kinase 3
Inhibitory Concentration 50
Mice
Adenosine Triphosphate
GSK-3
Cell Line, Tumor
CDC2-CDC28 Kinases
Animals
Humans
Urea
ASK1
c-Raf
Enzyme Inhibitors
Protein kinase A
Molecular Biology
Serine/threonine-specific protein kinase
Neurons
Cell Death
Dose-Response Relationship, Drug
Akt/PKB signaling pathway
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 5
Cell Biology
Cyclin-Dependent Kinases
Cell biology
Kinetics
Thiazoles
Models, Chemical
NIH 3T3 Cells
Peptides
Protein Binding
Signal Transduction
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Accession number :
- edsair.doi.dedup.....3603bf0acc51f06d47e3f21663b52801