title: Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.
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.
authors.affiliation: Department of Chemistry, Pharmacia Italia SpA, Discovery Research Oncology, Viale Pasteur, 10, 20014 Nerviano, Italy. jay.bertrand@pharmacia.com
authors.forename: J A
authors.initials: JA
authors.lastname: Bertrand
authors.forename: S
authors.initials: S
authors.lastname: Thieffine
authors.forename: A
authors.initials: A
authors.lastname: Vulpetti
authors.forename: C
authors.initials: C
authors.lastname: Cristiani
authors.forename: B
authors.initials: B
authors.lastname: Valsasina
authors.forename: S
authors.initials: S
authors.lastname: Knapp
authors.forename: H M
authors.initials: HM
authors.lastname: Kalisz
authors.forename: M
authors.initials: M
authors.lastname: Flocco
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D018716:Molecular Mimicry; D010766:Phosphorylation; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D001552:Benzazepines; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007211:Indoles; D008301:Maleimides; D017468:Receptors, Fibroblast Growth Factor; C120793:alsterpaullone; D000255:Adenosine Triphosphate; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D016203:CDC2 Protein Kinase; D038362:Glycogen Synthase Kinase 3; D019311:Staurosporine; C027185:indirubin