Open AccessAllosteric Inhibition of the Epidermal Growth Factor Receptor
Author(s) -
Julie K.-L. Sinclair,
Wesley E. Robertson,
Deepto Mozumdar,
Kim Quach,
Alanna Schepartz
Publication year - 2021
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.0c00978
Subject(s) - allosteric regulation , chemistry , epidermal growth factor receptor , epidermal growth factor , receptor , microbiology and biotechnology , biochemistry , biophysics , biology
We previously reported a family of hydrocarbon-stapled peptides designed to interact with the epidermal growth factor receptor (EGFR) juxtamembrane (JM) segment, blocking its ability to form a coiled coil dimer that is essential for receptor activation. These hydrocarbon-stapled peptides, most notably E1 S , decreased the proliferation of cell lines that express wild-type EGFR (H2030 and A431) as well as those expressing the oncogenic mutants EGFR L858R (H3255) and L858R/T790M (H1975). Although our previous investigations provided evidence that E1 S interacted with EGFR directly, the location and details of these interactions were not established. Here we apply biochemical and cross-linking mass spectrometry tools to better define the interactions between E1 S and EGFR. Taken with previously reported structure-activity relationships, our results support a model in which E1 S interacts simultaneously with both the JM and the C-lobe of the activator kinase, effectively displacing the JM of the receiver kinase. Our results also reveal potential interactions between E1 S and the N-terminal region of the C-terminal tail. We propose a model in which E1 S inhibits EGFR by both mimicking and inhibiting JM coiled coil formation. This model could be used to design novel, allosteric (and perhaps nonpeptidic) EGFR inhibitors.