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PDBsum entry 4ibm

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4ibm
Jmol
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 compl inhibitor irfin-1
Structure: Insulin receptor. Chain: a, b. Synonym: ir, insulin receptor subunit alpha, insulin recept 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    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1382 a.a.
301 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* 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.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    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.