Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27
- Author
- Katarzyna Skladanowska, Yehudi Bloch (UGent) , Jamie Strand, Kerry F. White, Jing Hua, Daniel Aldridge, Martin Welin, Derek T. Logan, Arne Soete (UGent) , Romain Merceron (UGent) , Casey Murphy, Mathias Provost (UGent) , J. Fernando Bazan, Christopher A. Hunter, Jonathan A. Hill and Savvas Savvides (UGent)
- Organization
- Project
-
- The molecular and structural basis of pro- and anti-inflammatory signalling assemblies mediated by IL-27 and IL-35.
- Towards the structural and molecular basis of pro-inflammatory signalling assemblies mediated by IL-23 and IL-12
- Towards the structural and molecular basis of signaling assemblies mediated by the pruritogenic Interleukin-31.
- Abstract
- Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Ra 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-27Ra 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-27Ra to juxtapose IL-27Ra to EBI3. This orients IL-27Ra 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-27Ra interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.
- Keywords
- CYTOKINE, PROTEIN, EXPRESSION, IL-27, COMPLEXES, SYSTEM
Downloads
-
4861 22Skladanowska.pdf
- full text (Published version)
- |
- open access
- |
- |
- 4.48 MB
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01GPB1P5CKE0A9JWFFKEVEAMZ8
- MLA
- Skladanowska, Katarzyna, et al. “Structural Basis of Activation and Antagonism of Receptor Signaling Mediated by Interleukin-27.” CELL REPORTS, vol. 41, no. 3, 2022, doi:10.1016/j.celrep.2022.111490.
- APA
- Skladanowska, K., Bloch, Y., Strand, J., White, K. F., Hua, J., Aldridge, D., … Savvides, S. (2022). Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27. CELL REPORTS, 41(3). https://doi.org/10.1016/j.celrep.2022.111490
- Chicago author-date
- Skladanowska, Katarzyna, Yehudi Bloch, Jamie Strand, Kerry F. White, Jing Hua, Daniel Aldridge, Martin Welin, et al. 2022. “Structural Basis of Activation and Antagonism of Receptor Signaling Mediated by Interleukin-27.” CELL REPORTS 41 (3). https://doi.org/10.1016/j.celrep.2022.111490.
- Chicago author-date (all authors)
- Skladanowska, Katarzyna, 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, and Savvas Savvides. 2022. “Structural Basis of Activation and Antagonism of Receptor Signaling Mediated by Interleukin-27.” CELL REPORTS 41 (3). doi:10.1016/j.celrep.2022.111490.
- Vancouver
- 1.Skladanowska K, Bloch Y, Strand J, White KF, Hua J, Aldridge D, et al. Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27. CELL REPORTS. 2022;41(3).
- IEEE
- [1]K. Skladanowska et al., “Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27,” CELL REPORTS, vol. 41, no. 3, 2022.
@article{01GPB1P5CKE0A9JWFFKEVEAMZ8,
abstract = {{Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Ra 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-27Ra 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-27Ra to juxtapose IL-27Ra to EBI3. This orients IL-27Ra 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-27Ra interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.}},
articleno = {{111490}},
author = {{Skladanowska, Katarzyna and Bloch, Yehudi and Strand, Jamie and White, Kerry F. and Hua, Jing and Aldridge, Daniel and Welin, Martin and Logan, Derek T. and Soete, Arne and Merceron, Romain and Murphy, Casey and Provost, Mathias and Bazan, J. Fernando and Hunter, Christopher A. and Hill, Jonathan A. and Savvides, Savvas}},
issn = {{2211-1247}},
journal = {{CELL REPORTS}},
keywords = {{CYTOKINE,PROTEIN,EXPRESSION,IL-27,COMPLEXES,SYSTEM}},
language = {{eng}},
number = {{3}},
pages = {{13}},
title = {{Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27}},
url = {{http://doi.org/10.1016/j.celrep.2022.111490}},
volume = {{41}},
year = {{2022}},
}
- Altmetric
- View in Altmetric
- Web of Science
- Times cited: