A structural mechanism for the generation of biased agonism in the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-a (TGF-), to the initiation of intracellular signaling pathways1-3. EGFR binds to EGF and TGF- with similar affinity but exhibits biased agonism, generating different signals from these ligands4-6. The mechanistic basis for this phenomenon remains unclear. We now present cryo-EM analyses of human EGFR bound to EGF and TGF-. We find, unexpectedly, that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal ends of the extracellular module are either juxtaposed or separated. EGF and TGF- differ in their ability to maintain the conformation with the membrane-proximal ends of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module is known to increase EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby providing a mechanism for the generation of biased agonism in this receptor family.