Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant

Metcalfe, RD; Hanssen, E; Fung, KY; Aizel, K; Kosasih, CC; Zlatic, CO; Doughty, L; Morton, CJ; Leis, AP; Parker, MW; Gooley, PR; Putoczki, TL; Griffin, MDW

Author(s): Metcalfe, RD; Hanssen, E; Fung, KY; Aizel, K; Kosasih, CC; Zlatic, CO; Doughty, L; Morton, CJ; Leis, AP; Parker, MW; Gooley, PR; Putoczki, TL; Griffin, MDW;
Details: Publication Year 2023-11-20,Volume 14,Issue #1,Page 7543
Journal Title: Nature Communications
Abstract: Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
Publisher: NPG
Keywords: Humans; *Cytokines; *Interleukin-11/genetics; Cytokine Receptor gp130/genetics; Interleukin-6/metabolism; Antigens, CD/metabolism; Membrane Glycoproteins/metabolism; Receptors, Interleukin-6/metabolism
Research Division(s): Personalised Oncology; Structural Biology
PubMed ID: 37985757
Publisher's Version: https://doi.org/10.1038/s41467-023-42754-w
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-42754-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-42754-w.pdf - (5.82MB, application/pdf)

Creation Date: 2023-11-30 09:13:30

Last Modified: 2023-11-30 09:35:31