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'''CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR''' | '''CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR''' | ||
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[[Category: Parang, K.]] | [[Category: Parang, K.]] | ||
[[Category: Till, J H.]] | [[Category: Till, J H.]] | ||
[[Category: | [[Category: Protein kinase inhibitor]] | ||
[[Category: | [[Category: Tyrosine kinase]] | ||
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Revision as of 14:21, 2 May 2008
CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR
Overview
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.
About this Structure
1GAG is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Mechanism-based design of a protein kinase inhibitor., Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA, Nat Struct Biol. 2001 Jan;8(1):37-41. PMID:11135668 Page seeded by OCA on Fri May 2 17:21:00 2008
