Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27

SummaryInterleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27R and gp130. To provide the structural framework for receptor activation by IL-27 and its emerging therapeutic targeting, we report here crystal structures of mouse IL-27 in complex with IL-27R and of human IL-27 in complex with SRF388, a monoclonal antibody undergoing clinical trials with oncology indications. One face of the helical p28 subunit interacts with EBI3, while the opposite face nestles into the interdomain elbow of IL-27R to juxtapose IL-27R to EBI3. This orients IL-27R for paired signaling with gp130, which only uses its immunoglobulin domain to bind to IL-27. Such a signaling complex is distinct from those mediated by IL-12 and IL-23. The SRF388 binding epitope on IL-27 overlaps with the IL-27R interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.Graphical abstractHighlights Mouse and human IL-27 adopt highly similar structures IL-27R interacts both with the p28 and EBI3 subunits of IL-27 SRF388 and IL-27R occupy mutually exclusive binding sites on IL-27 IL-27 mediates receptor assemblies distinct from IL-12 and IL-23Interleukin-27 (IL-27) activates its cognate receptors on cells to regulate innate and adaptive immune responses in T cell populations, an important area for basic and applied biomedicine. Sk adanowska and Bloch et al. report the structure and mechanism by which IL-27 binds its signaling receptors and show how a therapeutic antibody antagonizes IL-27 activity.