1GAG

CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR

Summary for 1GAG

• Entry DOI: 10.2210/pdb1gag/pdb
• Related: 1IR3
• Descriptor: INSULIN RECEPTOR, TYROSINE KINASE DOMAIN, BISUBSTRATE PEPTIDE INHIBITOR, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: protein kinase inhibitor, tyrosine kinase, transferase, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P06213
• Total number of polymer chains: 2
• Total formula weight: 36985.14

Authors

Parang, K.,Till, J.H.,Ablooglu, A.J.,Kohanski, R.A.,Hubbard, S.R.,Cole, P.A. (deposition date: 2000-11-29, release date: 2001-01-17, Last modification date: 2024-10-30)

Primary citation

Parang, K.,Till, J.H.,Ablooglu, A.J.,Kohanski, R.A.,Hubbard, S.R.,Cole, P.A.
Mechanism-based design of a protein kinase inhibitor.
Nat.Struct.Biol., 8:37-41, 2001

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. 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.

PubMed: 11135668
DOI: 10.1038/83028

Experimental method

X-RAY DIFFRACTION (2.7 Å)