PDBsum entry 4ibm

Transferase/transferase inhibitor

PDB id: 4ibm

Contents

Protein chain

301 a.a.

Ligands

IR1 ×2

Waters ×554

PDB id:

4ibm

Name:

Transferase/transferase inhibitor

Title:

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

Structure:

Insulin receptor. Chain: a, b. Synonym: ir, insulin receptor subunit alpha, insulin receptor subunit beta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.80Å R-factor: 0.184 R-free: 0.218

Authors:

J.Wu,T.Anastassiadis,K.C.Duong-Ly,J.R.Peterson

Key ref:

T.Anastassiadis et al. (2013). 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. PubMed id: 23935097 DOI: 10.1074/jbc.M113.505032

Date:

08-Dec-12 Release date: 21-Aug-13

Protein chains

P06213  (INSR_HUMAN) -  Insulin receptor from Homo sapiens

Seq: 1382 a.a.

Struc: 301 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M113.505032

J Biol Chem 288:28068-28077 (2013)

PubMed id: 23935097

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.

T.Anastassiadis, K.C.Duong-Ly, S.W.Deacon, A.Lafontant, H.Ma, K.Devarajan, R.L.Dunbrack, J.Wu, J.R.Peterson.

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.