PDBsum entry 4i23

Transferase

PDB id: 4i23

Contents

Protein chain

304 a.a.

Ligands

1C9

PDB id:

4i23

Name:

Transferase

Title:

Crystal structure of the wild-type egfr kinase domain in complex with dacomitinib (soaked)

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: unp residues 695-1022, egfr kinase domain. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.80Å R-factor: 0.229 R-free: 0.279

Authors:

K.S.Gajiwala,J.Feng,R.Ferre,K.Ryan,O.Brodsky,A.Stewart

Key ref:

K.S.Gajiwala et al. (2013). Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition. Structure, 21, 209-219. PubMed id: 23273428

Date:

21-Nov-12 Release date: 16-Jan-13

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 304 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

Structure 21:209-219 (2013)

PubMed id: 23273428

Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition.

K.S.Gajiwala, J.Feng, R.Ferre, K.Ryan, O.Brodsky, S.Weinrich, J.C.Kath, A.Stewart.

ABSTRACT

The oncogenicity of the L858R mutant form of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is thought to be due to the constitutive activation of its kinase domain. The selectivity of the marketed drugs gefitinib and erlotinib for L858R mutant is attributed to their specific recognition of the active kinase and to weaker ATP binding by L858R EGFR. We present crystal structures showing that neither L858R nor the drug-resistant L858R+T790M EGFR kinase domain is in the constitutively active conformation. Additional co-crystal structures show that gefitinib and dacomitinib, an irreversible anilinoquinazoline derivative currently in clinical development, may not be conformation specific for the active state of the enzyme. Structural data further reveal the potential mode of recognition of one of the autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase domain. Biochemical and biophysical evidence suggest that the oncogenic mutations impact the conformational dynamics of the enzyme.