Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.
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.
Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.
Jennifer
J
Stamos
Mark X
MX
Sliwkowski
Charles
C
Eigenbrot
D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D003461:Crystallography; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000069347:Erlotinib Hydrochloride; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D018411:Spodoptera
D004791:Enzyme Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors