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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27 Katarzyna Składanowska , Yehudi Bloch , Jamie Strand , Kerry F. White , Jing Hua , Daniel Aldridge , Martin Welin , Derek T. Logan , Arne Soete , Romain Merceron , Casey Murphy , Mathias Provost , J. Fernando Bazan , Christopher A. Hunter , Jonathan A. Hill , Savvas N. Savvidis Cell Reports 41 DOI: 10.1016/j.celrep.2022.111490 Diamond Proposal Number(s): [23282] Open Access Show Abstract ▼ Abstract: 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.	Oct 2022

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I04-Macromolecular Crystallography

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