1GAG: Crystal Structure Of The Insulin Receptor Kinase In Complex With A Bisubstrate Inhibitor

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.
PDB ID: 1GAGDownload
MMDB ID: 15335
PDB Deposition Date: 2000/11/29
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1GAG: dimeric; determined by author and by software (PISA)
Molecular Components in 1GAG
Label Count Molecule
Proteins (2 molecules)
Insulin Receptor, Tyrosine Kinase Domain(Gene symbol: INSR)
Molecule annotation
Bisubstrate Peptide Inhibitor
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB