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PDBsum entry 4jq7

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protein ligands links
Transferase/transferase inhibitor PDB id
4jq7
Jmol
Contents
Protein chain
303 a.a.
Ligands
KJQ
Waters ×25
PDB id:
4jq7
Name: Transferase/transferase inhibitor
Title: Crystal structure of egfr kinase domain in complex with comp
Structure: Epidermal growth factor receptor. Chain: a. Fragment: tyrosine kinase domain, unp residues 696-1021. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein erbb-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: hi5.
Resolution:
2.73Å     R-factor:   0.208     R-free:   0.237
Authors: Y.H.Peng,J.S.Wu
Key ref: Y.H.Peng et al. (2013). Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem, 56, 3889-3903. PubMed id: 23611691 DOI: 10.1021/jm400072p
Date:
20-Mar-13     Release date:   19-Jun-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.
303 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: 10.1021/jm400072p J Med Chem 56:3889-3903 (2013)
PubMed id: 23611691  
 
 
Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors.
Y.H.Peng, H.Y.Shiao, C.H.Tu, P.M.Liu, J.T.Hsu, P.K.Amancha, J.S.Wu, M.S.Coumar, C.H.Chen, S.Y.Wang, W.H.Lin, H.Y.Sun, Y.S.Chao, P.C.Lyu, H.P.Hsieh, S.Y.Wu.
 
  ABSTRACT  
 
The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.