Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 20. Nov., Seite 7543 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Metcalfe, Riley D [VerfasserIn] |
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| Links: |
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| Themen: |
133483-10-0 |
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| Anmerkungen: |
Date Completed 22.11.2023 Date Revised 23.11.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-42754-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364771496 |
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| 245 | 1 | 0 | |a Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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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| 650 | 7 | |a Interleukin-11 |2 NLM | |
| 650 | 7 | |a Cytokine Receptor gp130 |2 NLM | |
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| 700 | 1 | |a Fung, Ka Yee |e verfasserin |4 aut | |
| 700 | 1 | |a Aizel, Kaheina |e verfasserin |4 aut | |
| 700 | 1 | |a Kosasih, Clara C |e verfasserin |4 aut | |
| 700 | 1 | |a Zlatic, Courtney O |e verfasserin |4 aut | |
| 700 | 1 | |a Doughty, Larissa |e verfasserin |4 aut | |
| 700 | 1 | |a Morton, Craig J |e verfasserin |4 aut | |
| 700 | 1 | |a Leis, Andrew P |e verfasserin |4 aut | |
| 700 | 1 | |a Parker, Michael W |e verfasserin |4 aut | |
| 700 | 1 | |a Gooley, Paul R |e verfasserin |4 aut | |
| 700 | 1 | |a Putoczki, Tracy L |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Michael D W |e verfasserin |4 aut | |
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