Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase

J Biol Chem. 2004 Jul 23;279(30):31655-63. doi: 10.1074/jbc.M403319200. Epub 2004 Apr 29.


The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Aspartic Acid / chemistry
  • Benzamides
  • Catalytic Domain
  • Conserved Sequence
  • Crystallography, X-Ray
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Imatinib Mesylate
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Piperazines / pharmacology*
  • Protein Conformation
  • Proto-Oncogene Proteins c-kit / chemistry*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyrimidines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sequence Homology, Amino Acid
  • Static Electricity


  • Benzamides
  • Enzyme Inhibitors
  • Piperazines
  • Pyrimidines
  • Recombinant Proteins
  • Aspartic Acid
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • Receptor Protein-Tyrosine Kinases

Associated data

  • PDB/1T45
  • PDB/1T46