8DPU

The crystal structure of the IL-11 signalling complex

8DPU の概要

• エントリーDOI: 10.2210/pdb8dpu/pdb
• 分子名称: Interleukin-6 receptor subunit beta, Interleukin-11, Interleukin-11 receptor subunit alpha, ... (6 entities in total)
• 機能のキーワード: complex, gp130, glycoprotein 130, signalling, cancer, cytokine, cytokine-receptor complex
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 18
• 化学式量合計: 561230.71

構造登録者

Metcalfe, R.D.,Aizel, K.,Griffin, M.D.W. (登録日: 2022-07-17, 公開日: 2023-11-29, 最終更新日: 2024-10-16)

主引用文献

Metcalfe, R.D.,Hanssen, E.,Fung, K.Y.,Aizel, K.,Kosasih, C.C.,Zlatic, C.O.,Doughty, L.,Morton, C.J.,Leis, A.P.,Parker, M.W.,Gooley, P.R.,Putoczki, T.L.,Griffin, M.D.W.
Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant.
Nat Commun, 14:7543-7543, 2023

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 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.

PubMed: 37985757
DOI: 10.1038/s41467-023-42754-w

実験手法

X-RAY DIFFRACTION (3.78 Å)