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Title | Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 7543, Year 2023 |
Publish date | Nov 20, 2023 |
![]() | 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 / Michael D W Griffin / ![]() ![]() |
PubMed 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 ...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. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 1.48 - 4.0 Å |
Structure data | EMDB-27641, PDB-8dps: EMDB-27642, PDB-8dpt: ![]() PDB-8dpu: ![]() PDB-8dpv: ![]() PDB-8dpw: |
Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-SO4: ![]() ChemComp-CL: ![]() ChemComp-HOH: |
Source |
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![]() | CYTOKINE / complex / IL-6 family cytokine / gp130 / glycoprotein 130 / glycoprotein / signalling / cancer / CYTOKINE-RECEPTOR complex |