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

J Mol Biol. 2003 Oct 17;333(2):393-407. doi: 10.1016/j.jmb.2003.08.031.

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.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Antibiotics, Antineoplastic / pharmacology
  • Benzazepines / pharmacology
  • Binding Sites
  • Binding, Competitive
  • CDC2 Protein Kinase / metabolism
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / chemistry*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Growth Inhibitors / pharmacology
  • Humans
  • Indoles / pharmacology
  • Maleimides / pharmacology
  • Molecular Mimicry*
  • Phosphorylation
  • Protein Conformation
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / chemistry
  • Receptors, Fibroblast Growth Factor / metabolism
  • Staurosporine / pharmacology
  • Structure-Activity Relationship

Substances

  • Antibiotics, Antineoplastic
  • Benzazepines
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Indoles
  • Maleimides
  • Receptors, Fibroblast Growth Factor
  • alsterpaullone
  • Adenosine Triphosphate
  • FGFR1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • CDC2 Protein Kinase
  • Glycogen Synthase Kinase 3
  • Staurosporine
  • indirubin

Associated data

  • PDB/1PYX
  • PDB/1Q3D
  • PDB/1Q3W
  • PDB/1Q41
  • PDB/1Q4L