4IBM

Crystal structure of insulin receptor kinase domain in complex with an inhibitor Irfin-1

Summary for 4IBM

• Entry DOI: 10.2210/pdb4ibm/pdb
• Descriptor: Insulin receptor, 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3H-pyrazolo[3,4-c]pyridazin-3-one (3 entities in total)
• Functional Keywords: irk, kinase, atp binding, phosphorylation, membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P06213
• Total number of polymer chains: 2
• Total formula weight: 70272.21

Authors

Wu, J.,Anastassiadis, T.,Duong-Ly, K.C.,Peterson, J.R. (deposition date: 2012-12-08, release date: 2013-08-21, Last modification date: 2024-02-28)

Primary citation

Anastassiadis, T.,Duong-Ly, K.C.,Deacon, S.W.,Lafontant, A.,Ma, H.,Devarajan, K.,Dunbrack, R.L.,Wu, J.,Peterson, J.R.
A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.
J.Biol.Chem., 288:28068-28077, 2013

PubMed Abstract: Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.

PubMed: 23935097
DOI: 10.1074/jbc.M113.505032

Experimental method

X-RAY DIFFRACTION (1.8 Å)