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PDBsum entry 3w32

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protein ligands links
Transferase/transferase inhibitor PDB id
3w32
Jmol
Contents
Protein chain
317 a.a.
Ligands
W32
SO4
Waters ×82
PDB id:
3w32
Name: Transferase/transferase inhibitor
Title: Egfr kinase domain complexed with compound 20a
Structure: Epidermal growth factor receptor. Chain: a. 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. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
1.80Å     R-factor:   0.202     R-free:   0.236
Authors: S.Sogabe,Y.Kawakita
Key ref: Y.Kawakita et al. (2013). Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors. Bioorg Med Chem, 21, 2250-2261. PubMed id: 23490150 DOI: 10.1016/j.bmc.2013.02.014
Date:
07-Dec-12     Release date:   06-Mar-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.
317 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.bmc.2013.02.014 Bioorg Med Chem 21:2250-2261 (2013)
PubMed id: 23490150  
 
 
Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors.
Y.Kawakita, M.Seto, T.Ohashi, T.Tamura, T.Yusa, H.Miki, H.Iwata, H.Kamiguchi, T.Tanaka, S.Sogabe, Y.Ohta, T.Ishikawa.
 
  ABSTRACT  
 
A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered 6-substituted amide derivative 19b, which has a 1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3 nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding interactions with the main chain NH of Met793 and the side chain of Thr854 via a water-mediated hydrogen bond network, respectively. In addition, the NH proton at the 9-position makes an additional hydrogen bond with the carbonyl group of Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC50: 24/36 nM) and BT474 cell growth (GI50: 18 nM) inhibitory activities based on its pseudo-irreversible (PI) profile.