Fig. 3

The structural model of ligand-free head-to-head EGFR dimers. a An open-ended oligomer model of 9G8-bound EGFR extracellular domains in the inactive conformation built using the crystal contacts in the monomer structure in PDB ID 4KRP⁴², where 9G8-NB is coloured in cyan, EGFR DI in green, DII (red), DIII (blue), and DIV (grey). b A simulation-generated dimer structure of free EGFR extracellular domains and their TM domains in the lipid bilayer. The simulation was started from the crystal dimer of 9G8-bound EGFR extracellular domains in the tethered conformation in which the two copies of the 9G8-NB were removed from the simulation system. The images are based on the snapshot of the simulation at 20 µs. One of the two transmembrane helices is visible (left and middle panels). The right panel shows the dimer viewed from the membrane, where the trans interaction between DI and DII and the interaction between DIV and DIII are highlighted; the domains of monomer a and b are labelled. c By deleting residues 6–273 from the dimer structure in b, the dimer structure directly mapped to the EGFRvIII glioblastoma mutant. As shown, this dimer structure is likely not viable in EGFRvIII as the trans interaction between DI and DII is precluded by the deletion. d A simulation-generated dimer structure of 9G8-bound EGFR extracellular domains starting from a crystal dimer of 9G8-bound EGFR extracellular domains in the tethered conformation. These images are based on the snapshot of the simulation at 20 µs. Invisible from this image are the TM helices embedded in the membrane. The right panel shows the 9G8-bound dimer viewed from the membrane, where the trans-dimer interaction between DI and DII, and between DIV and DIII are highlighted