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Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27
DOI:
10.1016/j.celrep.2022.111490
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
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)