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PDBsum entry 4i23

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protein ligands links
Transferase PDB id
4i23
Jmol
Contents
Protein chain
304 a.a.
Ligands
1C9
PDB id:
4i23
Name: Transferase
Title: Crystal structure of the wild-type egfr kinase domain in com dacomitinib (soaked)
Structure: Epidermal growth factor receptor. Chain: a. Fragment: unp residues 695-1022, egfr kinase domain. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein erbb-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.80Å     R-factor:   0.229     R-free:   0.279
Authors: K.S.Gajiwala,J.Feng,R.Ferre,K.Ryan,O.Brodsky,A.Stewart
Key ref: K.S.Gajiwala et al. (2013). Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition. Structure, 21, 209-219. PubMed id: 23273428 DOI: 10.1016/j.str.2012.11.014
Date:
21-Nov-12     Release date:   16-Jan-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
304 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.str.2012.11.014 Structure 21:209-219 (2013)
PubMed id: 23273428  
 
 
Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition.
K.S.Gajiwala, J.Feng, R.Ferre, K.Ryan, O.Brodsky, S.Weinrich, J.C.Kath, A.Stewart.
 
  ABSTRACT  
 
The oncogenicity of the L858R mutant form of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is thought to be due to the constitutive activation of its kinase domain. The selectivity of the marketed drugs gefitinib and erlotinib for L858R mutant is attributed to their specific recognition of the active kinase and to weaker ATP binding by L858R EGFR. We present crystal structures showing that neither L858R nor the drug-resistant L858R+T790M EGFR kinase domain is in the constitutively active conformation. Additional co-crystal structures show that gefitinib and dacomitinib, an irreversible anilinoquinazoline derivative currently in clinical development, may not be conformation specific for the active state of the enzyme. Structural data further reveal the potential mode of recognition of one of the autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase domain. Biochemical and biophysical evidence suggest that the oncogenic mutations impact the conformational dynamics of the enzyme.