Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor.
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.
Schindler
T
T
Laboratories of Molecular Biophysics, Rockefeller University, New York, New York 10021, USA.
Sicheri
F
F
Pico
A
A
Gazit
A
A
Levitzki
A
A
Kuriyan
J
J
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003461:Crystallography; D007313:Insecta; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D018909:src Homology Domains / Q000502:physiology
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051572:Proto-Oncogene Proteins c-hck; D016392:Proto-Oncogene Proteins pp60(c-src)