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Crystal Structure of Hck in Complex with a Src
Family-Selective Tyrosine Kinase Inhibitor


Thomas Schindler, Frank Sicheri, Alexander Pico, Aviv Gazit, Alexander Levitzki, John Kuriyan

Molecular Cell, Vol. 3, 639-648, May, 1999

The crystal structure of the autoinhibited form of Hck has been determined at 2.0 Å 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.

Coordinates for the Hck-PP1 Complex
Coordinates will also be available from the Protein Databank with code: 1qcf.

Images (Click on the small image to get a large one):

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