Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor

Mol Cell. 1999 May;3(5):639-48. doi: 10.1016/s1097-2765(00)80357-3.


The crystal structure of the autoinhibited form of Hck has been determined at 2.0 A resolution, in complex with a specific pyrazolo pyrimidine-type inhibitor, PP1. The activation segment, a key regulatory component of the catalytic domain, is unphosphorylated and is visualized in its entirety. Tyr-416, the site of activating autophosphorylation in the Src family kinases, is positioned such that access to the catalytic machinery is blocked. PP1 is bound at the ATP-binding site of the kinase, and a methylphenyl group on PP1 is inserted into an adjacent hydrophobic pocket. The enlargement of this pocket in autoinhibited Src kinases suggests a route toward the development of inhibitors that are specific for the inactive forms of these proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Crystallography
  • Insecta
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding / physiology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-hck
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
  • Proto-Oncogene Proteins pp60(c-src) / chemistry*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • src Homology Domains / physiology


  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-hck
  • Proto-Oncogene Proteins pp60(c-src)

Associated data

  • PDB/1QCF