Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface

摘要: Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical activation is formation an asymmetric dimer by intracellular kinase domains, which carboxy-terminal lobe (C lobe) one domain induces active conformation other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with inhibits domains EGFR ERBB2 (refs 3-5). Crystal structures complexes between a fragment show that approximately 25-residue epitope (segment 1) from binds to distal surface C domain. Biochemical cell-based analyses confirm this interaction contributes blocking activating interface. A longer peptide extended terminal segment 1 has increased potency inhibitor activated domain, while retaining critical dependence on 1. We signalling molecules contain constitutively still requires dimer, underscoring importance interface blockage MIG6-mediated inhibition.