Download MendeleyStructural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors
Bertrand, J.A., Thieffine, S., Vulpetti, A., Cristiani, C., Valsasina, B., Knapp, S., Kalisz, H.M., Flocco, M.(2003) J Mol Biol 333: 393-407
- PubMed: 14529625
- DOI: https://doi.org/10.1016/j.jmb.2003.08.031
- Primary Citation of Related Structures:
1PYX, 1Q3D, 1Q3W, 1Q41, 1Q4L - PubMed 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.
Organizational Affiliation:
Department of Chemistry, Pharmacia Italia SpA, Discovery Research Oncology, Viale Pasteur, 10, 20014 Nerviano, Italy. [email protected]
