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

DOI: 10.1016/j.celrep.2022.111490 DOI Help

Authors: Katarzyna Składanowska (Ghent University; VIB-UGent Center for Inflammation Research) , Yehudi Bloch (Ghent University; VIB-UGent Center for Inflammation Research) , Jamie Strand (Surface Oncology) , Kerry F. White (Surface Oncology) , Jing Hua (Surface Oncology) , Daniel Aldridge (University of Pennsylvania) , Martin Welin (SARomics Biostructures AB) , Derek T. Logan (SARomics Biostructures AB) , Arne Soete (Ghent University; VIB-UGent Center for Inflammation Research) , Romain Merceron (Ghent University; VIB-UGent Center for Inflammation Research) , Casey Murphy (Ghent University; VIB-UGent Center for Inflammation Research) , Mathias Provost (Ghent University; VIB-UGent Center for Inflammation Research) , J. Fernando Bazan (VIB-UGent Center for Inflammation Research; ħ Bioconsulting) , Christopher A. Hunter (University of Pennsylvania) , Jonathan A. Hill (Surface Oncology) , Savvas N. Savvidis (Ghent University; VIB-UGent Center for Inflammation Research)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Cell Reports , VOL 41

State: Published (Approved)
Published: October 2022
Diamond Proposal Number(s): 23282

Open Access Open Access

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.

Journal Keywords: cytokine-receptor complex; cytokine-antibody complex; immunotherapy; signaling; antagonism; IL-27; IL-27Rα; gp130; therapeutic antibody; IL-12 family

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: P14 at PETRA III; Proxima2A at SOLEIL

Added On: 26/10/2022 09:27

Documents:
1-s2.0-S2211124722013407-main.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)