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Structure paper

TitleStructures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 7543, Year 2023
Publish dateNov 20, 2023
AuthorsRiley 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 AbstractInterleukin (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.
External linksNat Commun / PubMed:37985757 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.48 - 4.0 Å
Structure data

27641

8dps

EMDB-27641, PDB-8dps:
The structure of the interleukin 11 signalling complex, truncated gp130
Method: EM (single particle) / Resolution: 3.47 Å

27642

8dpt

EMDB-27642, PDB-8dpt:
The structure of the IL-11 signalling complex, with full-length extracellular gp130
Method: EM (single particle) / Resolution: 4.0 Å

PDB-8dpu:
The crystal structure of the IL-11 signalling complex
Method: X-RAY DIFFRACTION / Resolution: 3.78 Å

PDB-8dpv:
The crystal structure of Interleukin-11, W147A mutant
Method: X-RAY DIFFRACTION / Resolution: 1.48 Å

PDB-8dpw:
The structure of Interleukin-11 Mutein
Method: X-RAY DIFFRACTION / Resolution: 1.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-SO4:
SULFATE ION

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsCYTOKINE / complex / IL-6 family cytokine / gp130 / glycoprotein 130 / glycoprotein / signalling / cancer / CYTOKINE-RECEPTOR complex

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