1M17

Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib

Summary for 1M17

• Entry DOI: 10.2210/pdb1m17/pdb
• Related: 1M14
• Descriptor: epidermal growth factor receptor, [6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE (3 entities in total)
• Functional Keywords: transferase, tyrosine kinase domain
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38269.19

Authors

Stamos, J.,Sliwkowski, M.X.,Eigenbrot, C. (deposition date: 2002-06-17, release date: 2002-09-04, Last modification date: 2024-02-14)

Primary citation

Stamos, J.,Sliwkowski, M.X.,Eigenbrot, C.
Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.
J.Biol.Chem., 277:46265-46272, 2002

PubMed 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.

PubMed: 12196540
DOI: 10.1074/jbc.M207135200

Experimental method

X-RAY DIFFRACTION (2.6 Å)