(A) Ribbon representation of the IL-27 quaternary signaling complex, containing gp130 (red), p28 (blue), Epstein-Barr Virus-Induced 3 (Ebi3; purple), and IL-27Rα (green). Regions containing sites 1, 2, and 3 are boxed in purple, green, and red, respectively. (B) Two views of the site 1 interface, colored as in (A). (C) The site 2 interface, composed of a site 2a, p28 to IL-27Rα, interaction, and a site 2b, Ebi3 to IL-27Rα, interaction. All proteins are colored as in (A). (D,E) The site 3 interface, composed of a site 3a, p28 to gp130, interaction, and a site 3b, Ebi3 to IL-27Rα, interaction. All proteins are colored as in (A). (F) Structural overlay of site 3 interacting domains from IL-27 complex, IL-6 complex (PDB 1P9M), and viral IL-6 (vIL-6) complex (PDB 1L1R). IL-27 quaternary complex colored as in (A), IL-6 ternary complex in orange (IL-6) and yellow (gp130), and vIL-6 binary complex in green (vIL-6) and teal (gp130).