Mechanism-based design of a protein kinase inhibitor

Nat Struct Biol. 2001 Jan;8(1):37-41. doi: 10.1038/83028.


Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding Sites
  • Catalytic Domain
  • Chickens
  • Crystallography, X-Ray
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism*
  • Hydrogen Bonding
  • Kinetics
  • Magnesium / metabolism
  • Models, Molecular
  • Peptides / chemistry
  • Peptides / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, Insulin / antagonists & inhibitors*
  • Receptor, Insulin / chemistry
  • Receptor, Insulin / metabolism*
  • Substrate Specificity


  • Enzyme Inhibitors
  • Peptides
  • adenosine 5'-O-(3-thiotriphosphate)
  • Adenosine Triphosphate
  • Receptor, Insulin
  • Cyclic AMP-Dependent Protein Kinases
  • Magnesium

Associated data

  • PDB/1GAG