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Updated: Aug 30, 2026

Modeling an Enzyme Active Site using Molecular Visualization Freeware
Published on: December 25, 2021
Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors
J A Bertrand1, S Thieffine, A Vulpetti
1Department of Chemistry, Pharmacia Italia SpA, Discovery Research Oncology, Viale Pasteur, 10, 20014 Nerviano, Italy. jay.bertrand@pharmacia.com
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.
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