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 ATPγS 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.
Original language | English (US) |
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Pages (from-to) | 37-41 |
Number of pages | 5 |
Journal | Nature Structural Biology |
Volume | 8 |
Issue number | 1 |
DOIs | |
State | Published - 2001 |
Externally published | Yes |
ASJC Scopus subject areas
- Structural Biology
- Biochemistry
- Genetics