Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27
(2022) In Cell Reports 41(3).- 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... (More)
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.
(Less)
- author
- publishing date
- 2022-10-18
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Reports
- volume
- 41
- issue
- 3
- article number
- 111490
- pages
- 21 pages
- publisher
- Cell Press
- external identifiers
-
- pmid:36261006
- scopus:85140043997
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2022.111490
- language
- English
- LU publication?
- no
- additional info
- Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
- id
- ef626d66-3e55-4bc7-823d-92b8d3c28452
- date added to LUP
- 2022-10-21 13:07:42
- date last changed
- 2024-06-13 21:54:35
@article{ef626d66-3e55-4bc7-823d-92b8d3c28452, abstract = {{<p>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.</p>}}, author = {{Składanowska, 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 N.}}, issn = {{2211-1247}}, language = {{eng}}, month = {{10}}, number = {{3}}, publisher = {{Cell Press}}, series = {{Cell Reports}}, title = {{Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27}}, url = {{http://dx.doi.org/10.1016/j.celrep.2022.111490}}, doi = {{10.1016/j.celrep.2022.111490}}, volume = {{41}}, year = {{2022}}, }