Journal article
Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
RD Metcalfe, E Hanssen, KY Fung, K Aizel, CC Kosasih, CO Zlatic, L Doughty, CJ Morton, AP Leis, MW Parker, PR Gooley, TL Putoczki, MDW Griffin
Nature Communications | Published : 2023
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 inhibit..
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Awarded by State Government of Victoria
Funding Acknowledgements
Parts of this research were conducted at the SAXS/WAXS and MX2 beamlines of the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organisation, and made use of the ACRF Detector at the MX2 beamline. Initial crystallisation screens were conducted at the CSIRO Collaborative Crystallisation Centre, Melbourne, Australia. This research made use of the ACRF Facility for Innovative Cancer Drug Discovery and the LIEF HPC-GPGPU Facility hosted at the University of Melbourne (LE170100200). We acknowledge the Ian Holmes Imaging Centre, the Melbourne Protein Characterisation Platform, and the Melbourne Mass Spectrometry and Proteomics Facility, at the Bio21 Molecular Science and Biotechnology Institute, for exceptional technical support. This work was supported by the National Health & Medical Research Council of Australia (APP1147621, APP1080498 to M.D.W.G. and T.L.P.), Cancer Council New South Wales (RG 22-01 to M.D.W.G. and T.L.P.), and the Australian Research Council (DP230102422 to M.D.W.G. and T.L.P.). R.D.M. was the recipient of an Australian Government Research Training Program Scholarship. M.W.P. is an NHMRC Investigator Fellow (APP1194263). T.L.P. is the recipient of a Sylvia and Charles Viertel Senior Medical Research Fellowship. Funding from the Victorian State Government Operational Infrastructure Support Scheme is acknowledged.