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bioRxiv · 10.1101/2022.07.21.500383

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

Metcalfe, R. D.·Hanssen, E.·Fung, K. Y.·Aizel, K.·Kosasih, C. C.·Zlatic, C. O.·Doughty, L.·Morton, C. J.·Leis, A. P.·Parker, M. W.·Gooley, P. R.·Putoczki, T. L.·Griffin, M. D. W.
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Abstract

Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in numerous autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors is lacking. Here we present cryo-EM and crystal structures of the IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family {beta}-receptor, gp130. We show that the membrane-proximal domains of gp130 are dynamic and do not participate in complex assembly. We demonstrate that the cytokine mutant IL-11 Mutein competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibitory activity 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.

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Metcalfe, R. D., Hanssen, E., Fung, K. Y., Aizel, K., Kosasih, C. C., Zlatic, C. O., Doughty, L., Morton, C. J., Leis, A. P., Parker, M. W., Gooley, P. R., Putoczki, T. L., Griffin, M. D. W.. 2022-07-22. Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant. https://doi.org/10.1101/2022.07.21.500383

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