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

Riley D. Metcalfe, Eric Hanssen, Ka Yee Fung, Kaheina Aizel, Clara C. Kosasih, Courtney O. Zlatic, Larissa Doughty, Craig J. Morton, Andrew P. Leis, Michael W. Parker, Paul R. Gooley, Tracy L. Putoczki and Michael D. W. Griffin ()
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Riley D. Metcalfe: University of Melbourne, Parkville
Eric Hanssen: University of Melbourne, Parkville
Ka Yee Fung: Walter and Eliza Hall Institute of Medical Research, Parkville
Kaheina Aizel: University of Melbourne, Parkville
Clara C. Kosasih: University of Melbourne, Parkville
Courtney O. Zlatic: University of Melbourne, Parkville
Larissa Doughty: University of Melbourne, Parkville
Craig J. Morton: University of Melbourne, Parkville
Andrew P. Leis: University of Melbourne, Parkville
Michael W. Parker: University of Melbourne, Parkville
Paul R. Gooley: University of Melbourne, Parkville
Tracy L. Putoczki: Walter and Eliza Hall Institute of Medical Research, Parkville
Michael D. W. Griffin: University of Melbourne, Parkville

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42754-w

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