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 Angstrom 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 kin ases, 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 gro up on PP1 is inserted into an adjacent hydrophobic pocket. The enlargement of this pocket in autoinhibited Src kinases suggests a route toward the dev elopment of inhibitors that are specific for the inactive forms of these pr oteins.