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.
Keywords
Epidermal growth factor receptorProtein kinase domainDomain (mathematical analysis)KinaseCell biologyChemistryBiologyReceptorBiochemistryMathematicsGene
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Publication Info
- Year
- 2002
- Type
- article
- Volume
- 277
- Issue
- 48
- Pages
- 46265-46272
- Citations
- 1443
- Access
- Closed
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Cite This
Jennifer L. Stamos,
Mark X. Sliwkowski,
Charles Eigenbrot
(2002).
Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor.
Journal of Biological Chemistry
, 277
(48)
, 46265-46272.
https://doi.org/10.1074/jbc.m207135200
Identifiers
- DOI
- 10.1074/jbc.m207135200