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The structure of Interleukin-11 Mutein
Structural highlights
FunctionIL11_HUMAN Directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production. Publication Abstract from PubMedInterleukin (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 beta-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. 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 Nat Commun. 2023 Nov 20;14(1):7543. doi: 10.1038/s41467-023-42754-w. PMID:37985757[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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