(A) Left: the four members of the human EGFR family, each consisting of an ectodomain, a single-pass transmembrane helix, and an intracellular module that includes a kinase domain. As shown, Her2 bears a closed ligand binding site and does not bind EGF-like ligands. Her3 is kinase-dead, and its intracellular module is thus colored gray. Right: common homo- and heterodimers of the EGFR family. The Her2 homodimer is rendered semitransparent to indicate its instability in normal cell conditions. (B) Schematic of the ligand-free Her2 ectodomain monomer, as observed crystallographically (PDB entries 1N8Z, 2A91, 1S78, 3N85, and 3MZW). Domain II is bent. (C) Schematic of the crystal structure of the 2-ligand EGFR ectodomain dimer (PDB entry 1NJP). The dimer is symmetric, and domain II is straight in both subunits. (D) Schematic of the crystal structure of the dEGFR ectodomain dimer (PDB entry 3LTF). Although Spitz ligands are bound to both subunits, the structure is asymmetric; domain II is straight in one subunit but bent in the other. Domain V and part of domain IV were not resolved in this crystal structure and are not shown in the schematic. The conformations of the bent and straight domain IIs in (B), (C), and (D) are indicated by the black lines.