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

Katarzyna Składanowska1, Yehudi Bloch1, Jamie Strand2

  • 1Unit for Structural Biology, Department of Biochemistry and Microbiology Ghent University, Technologiepark 71, 9052 Ghent, Belgium; Unit for Structural Biology, VIB-UGent Center for Inflammation Research, Technologiepark 71, 9052 Ghent, Belgium.

Cell Reports
|October 19, 2022
PubMed

Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Rα 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-27Rα 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-27Rα to juxtapose IL-27Rα to EBI3. This orients IL-27Rα 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-27Rα interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.

Keywords:
CP: ImmunologyIL-12 familyIL-27IL-27Rαantagonismcytokine-antibody complexcytokine-receptor complexgp130immunotherapysignalingtherapeutic antibody

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