1GAG

Mechanism-based design of a protein kinase inhibitor.

(2001) Nat Struct Biol 8: 37-41

• PubMed: 11135668 Search on PubMed
• DOI: 10.1038/83028
• Primary Citation of Related Structures:  
  1GAG


• PubMed Abstract: 
  

Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer ...

Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors.

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Related Citations: 

• Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog
  Hubbard, S.R.
  (1997) EMBO J 16: 5572

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Organizational Affiliation: 

The Johns Hopkins University School of Medicine, Department of Pharmacology Molecular Sciences, Baltimore, Maryland 21205, USA.


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