PDBsum entry 4ll0

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Transferase/transferase inhibitor PDB id
Protein chains
291 a.a.
YUN ×2
PDB id:
Name: Transferase/transferase inhibitor
Title: Egfr l858r/t790m in complex with pd168393
Structure: Epidermal growth factor receptor. Chain: a, b. Fragment: egfr (unp residues 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
4.00Å     R-factor:   0.238     R-free:   0.257
Authors: C.H.Yun,M.J.Eck
Key ref: M.Red Brewer et al. (2013). Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci U S A, 110, E3595. PubMed id: 24019492 DOI: 10.1073/pnas.1220050110
09-Jul-13     Release date:   11-Sep-13    
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Protein chains
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
1210 a.a.
291 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [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     regulation of signal transduction   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  


DOI no: 10.1073/pnas.1220050110 Proc Natl Acad Sci U S A 110:E3595 (2013)
PubMed id: 24019492  
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer.
M.Red Brewer, C.H.Yun, D.Lai, M.A.Lemmon, M.J.Eck, W.Pao.
The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a "donor" tyrosine kinase domain (TKD) contacts an "acceptor" TKD, leading to its activation. In the context of a ligand-induced dimer, identical wild-type EGFR TKDs are thought to assume the donor or acceptor roles in a random manner. Here, we present biochemical reconstitution data demonstrating that activated EGFR mutants found in lung cancer preferentially assume the acceptor role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association with WT EGFR, leading to hyperphosphorylation of the WT counterpart. Mutated EGFRs also hyperphosphorylate the related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, in a similar manner. This directional "superacceptor activity" is particularly pronounced in the drug-resistant L834R/T766M mutant. A 4-Å crystal structure of this mutant in the active conformation reveals an asymmetric dimer interface that is essentially the same as that in WT EGFR. Asymmetric dimer formation induces an allosteric conformational change in the acceptor subunit. Thus, superacceptor activity likely arises simply from a lower energetic cost associated with this conformational change in the mutant EGFR compared with WT, rather than from any structural alteration that impairs the donor role of the mutant. Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit.