Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor

J Biol Chem. 2002 Nov 29;277(48):46265-72. doi: 10.1074/jbc.M207135200. Epub 2002 Aug 23.

Abstract

The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Catalytic Domain
  • Cell Line
  • Crystallography
  • Enzyme Activation
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / chemistry*
  • Erlotinib Hydrochloride
  • Models, Molecular
  • Molecular Structure
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Spodoptera

Substances

  • Enzyme Inhibitors
  • Quinazolines
  • Erlotinib Hydrochloride
  • ErbB Receptors

Associated data

  • PDB/1M14
  • PDB/1M17