1. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.
- Author
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Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, and Flocco M
- Subjects
- Antibiotics, Antineoplastic pharmacology, Benzazepines pharmacology, Binding Sites, Binding, Competitive, CDC2 Protein Kinase metabolism, Crystallography, X-Ray, Glycogen Synthase Kinase 3 antagonists & inhibitors, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Growth Inhibitors pharmacology, Humans, Indoles pharmacology, Maleimides pharmacology, Phosphorylation, Protein Conformation, Receptor Protein-Tyrosine Kinases chemistry, Receptor Protein-Tyrosine Kinases metabolism, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor chemistry, Receptors, Fibroblast Growth Factor metabolism, Staurosporine pharmacology, Structure-Activity Relationship, Adenosine Triphosphate metabolism, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 chemistry, Molecular Mimicry
- Abstract
GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.
- Published
- 2003
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