Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Cells, Cultured
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Crystallography
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Insecta
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Molecular Sequence Data
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Phosphorylation
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Protein Binding / physiology
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / chemistry*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-hck
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Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
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Proto-Oncogene Proteins pp60(c-src) / chemistry*
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Sequence Homology, Amino Acid
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Substrate Specificity
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src Homology Domains / physiology
Substances
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Proto-Oncogene Proteins
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-hck
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Proto-Oncogene Proteins pp60(c-src)