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PDBsum entry 2eb3

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protein ligands links
Transferase PDB id
2eb3
Jmol
Contents
Protein chain
294 a.a. *
Ligands
ANP
Waters ×1
* Residue conservation analysis
PDB id:
2eb3
Name: Transferase
Title: Crystal structure of mutated egfr kinase domain (l858r) in c with amppnp
Structure: Epidermal growth factor receptor. Chain: a. Fragment: kinase domain, unp residues 695-1022. Synonym: receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.84Å     R-factor:   0.190     R-free:   0.236
Authors: S.Yoshikawa,M.Kukimoto-Niino,M.Shirouzu,K.Senba,T.Yamamoto, S.Yokoyama,Riken Structural Genomics/proteomics Initiative
Key ref: S.Yoshikawa et al. (2013). Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene, 32, 27-38. PubMed id: 22349823
Date:
06-Feb-07     Release date:   12-Feb-08    
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.
294 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
Bound ligand (Het Group name = ANP)
matches with 81.25% similarity
+ [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    
 
 
Oncogene 32:27-38 (2013)
PubMed id: 22349823  
 
 
Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor.
S.Yoshikawa, M.Kukimoto-Niino, L.Parker, N.Handa, T.Terada, T.Fujimoto, Y.Terazawa, M.Wakiyama, M.Sato, S.Sano, T.Kobayashi, T.Tanaka, L.Chen, Z.J.Liu, B.C.Wang, M.Shirouzu, S.Kawa, K.Semba, T.Yamamoto, S.Yokoyama.
 
  ABSTRACT  
 
The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.