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PDBsum entry 4g5p

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4g5p
Jmol
Contents
Protein chains
299 a.a.
Ligands
0WN
Waters ×38
PDB id:
4g5p
Name: Transferase/transferase inhibitor
Title: Crystal structure of egfr kinase t790m in complex with bibw2
Structure: Epidermal growth factor receptor. Chain: a, b. Fragment: kinase domain, unp residues 696-1022. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein erbb-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
3.17Å     R-factor:   0.247     R-free:   0.323
Authors: F.Solca,G.Dahl,A.Zoephel,G.Bader,M.Sanderson,C.Klein,O.Kraem F.Himmelsbach,E.Haaksma,G.R.Adolf
Key ref: F.Solca et al. (2012). Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther, 343, 342-350. PubMed id: 22888144 DOI: 10.1124/jpet.112.197756
Date:
18-Jul-12     Release date:   29-Aug-12    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
299 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

 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: 10.1124/jpet.112.197756 J Pharmacol Exp Ther 343:342-350 (2012)
PubMed id: 22888144  
 
 
Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.
F.Solca, G.Dahl, A.Zoephel, G.Bader, M.Sanderson, C.Klein, O.Kraemer, F.Himmelsbach, E.Haaksma, G.R.Adolf.
 
  ABSTRACT  
 
Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide] is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFR(L858R/T790M), human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC(50) = 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide (BI 37781), a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFR(L858R), but less or no detectable activity on cells expressing EGFR(L858R/ T790M) HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."