Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry

Chem Biol. 2010 Nov 24;17(11):1241-9. doi: 10.1016/j.chembiol.2010.09.010.


Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit / metabolism
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / chemistry
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3 / metabolism


  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Proto-Oncogene Proteins c-kit
  • Receptor, Macrophage Colony-Stimulating Factor
  • Receptor, Platelet-Derived Growth Factor beta
  • fms-Like Tyrosine Kinase 3
  • Proto-Oncogene Proteins c-abl