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spinqualitylabelsall models 1pyx, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

GSK-3 Beta complexed with AMP-PNP

Overview

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.

About this Structure

1PYX is a Single protein structure of sequence from Homo sapiens with MG and ANP as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

Reference

Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors., Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M, J Mol Biol. 2003 Oct 17;333(2):393-407. PMID:14529625

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