Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor*

By J. Stamos, M. Sliwkowski, C. Eigenbrot. Journal of Biological Chemistry, 2002

1,329 citations recorded by the source corpus.

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-Å 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, TarcevaTM). 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.

Subfields: Genetics, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/7f87054105191bb29db0a31791f9adf2372d9845

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Citations in the corpus

An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. (2006, background): “The unit cell parameters for these crystals are very similar to those for the original form A crystals, which were obtained under different conditions (1 M Na/K tartrate, 100 mM MES, pH 7.0) (Stamos et al., 2002).”
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment (2009, neutral): “…tail (residues 967 to 983) that is of interest here is mainly disordered in structures of the active conformation of the EGFR kinase domain (Stamos et al., 2002) and is partially ordered but in a different conformation in the other inactive structures (Wood et al., 2004; Zhang et al.,…”
An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. (2003, background): “…no significant (static) structural differences are found between the EGF-bound and The crystal structure of the unphosphorylated EGFR kinase domain (Stamos et al., 2002) suggests one expla-unliganded states of domain III (Ferguson et al., 2003; Ogiso et al., 2002) argues against this possibility.”
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways (2017, background): “The tyrosine kinase domain can be divided into an N-lobe (mainly a β-sheet structure) and a C-lobe (a mainly α-helical structure), with an ATP-binding site located between the two lobes [71].”
The epidermal growth factor receptor family: Biology driving targeted therapeutics (2008, background): “Multiple signal transduction pathways lie downstream of activated EGFRs and have been reviewed elsewhere [2, 37] (Fig.”
Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. (2004, background): “ErbB2 is the only ErbB for which no ligand has been found; the structure of the ErbB2 extracellular domain shows domain of EGFR (Stamos et al., 2002).”
Strong and Weak Hydrogen Bonds in Protein–Ligand Recognition (2019, methodology): “The docking of ligands for the VS was done in the active site as obtained in the experimental crystal structure of the erlotinib–EGFR complex.(45) Erlotinib is an anti-cancer drug from Genentech, belonging to the 4-anilinoquinazoline class.”
Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker (2012, methodology): “A published model of EGFR (Protein Data Bank ID code 1M17) (Stamos et al., 2002) was used as a search model.”
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. (2007, methodology): “The binding mode of gefitinib is strikingly similar to that previously reported for erlotinib (Stamos et al., 2002) (Figure S2).”
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP (2008, background): “The quinoline core of HKI-272 forms a single hydrogen bond with the hinge region of the kinase in a manner analogous to anilinoquinazoline compounds (31, 32).”