Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.

Journal article

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.

Authors: Bertrand, J; Thieffine, S; Vulpetti, A; Cristiani, C; Valsasina, B

• Publication status: Published
• Journal: Journal of molecular biology
• Volume: 333
• Issue: 2
• Pages: 393-407
• Publication date: 2003-10-01
• DOI: 10.1016/j.jmb.2003.08.031
• EISSN: 1089-8638
• ISSN: 0022-2836
• Language: English
• Keywords: Adenosine Triphosphate; Indoles; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor; Receptor Protein-Tyrosine Kinases; Crystallography, X-Ray; Binding Sites; Enzyme Inhibitors; Benzazepines; Phosphorylation; Staurosporine; Growth Inhibitors; Binding, Competitive; Molecular Mimicry; Structure-Activity Relationship; Glycogen Synthase Kinase 3; Humans; Protein Conformation; Maleimides; CDC2 Protein Kinase; Antibiotics, Antineoplastic