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PDBsum entry 4lqm

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protein ligands metals links
Transferase/transferase inhibitor PDB id
4lqm
Jmol
Contents
Protein chain
305 a.a.
Ligands
DJK
Metals
_CL ×2
Waters ×125
PDB id:
4lqm
Name: Transferase/transferase inhibitor
Title: Egfr l858r in complex with pd168393
Structure: Epidermal growth factor receptor. Chain: a. Fragment: epidermal growth factor receptor 694-1022. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein erbb-1. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.50Å     R-factor:   0.187     R-free:   0.228
Authors: C.H.Yun,M.J.Eck
Key ref: H.Yasuda et al. (2013). Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med, 5, 216ra177. PubMed id: 24353160 DOI: 10.1126/scitranslmed.3007205
Date:
19-Jul-13     Release date:   15-Jan-14    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
305 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
+ [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: 10.1126/scitranslmed.3007205 Sci Transl Med 5:216ra177 (2013)
PubMed id: 24353160  
 
 
Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
H.Yasuda, E.Park, C.H.Yun, N.J.Sng, A.R.Lucena-Araujo, W.L.Yeo, M.S.Huberman, D.W.Cohen, S.Nakayama, K.Ishioka, N.Yamaguchi, M.Hanna, G.R.Oxnard, C.S.Lathan, T.Moran, L.V.Sequist, J.E.Chaft, G.J.Riely, M.E.Arcila, R.A.Soo, M.Meyerson, M.J.Eck, S.S.Kobayashi, D.B.Costa.
 
  ABSTRACT  
 
Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.