Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant

13Citations
Citations of this article
35Readers
Mendeley users who have this article in their library.

This article is free to access.

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.

References Powered by Scopus

35319Citations
14202Readers
Get full text

Features and development of Coot

21305Citations
6069Readers

This article is free to access.

Phaser crystallographic software

16599Citations
4407Readers

This article is free to access.

Cited by Powered by Scopus

11Citations
37Readers

This article is free to access.

Get full text

This article is free to access.

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Metcalfe, R. D., Hanssen, E., Fung, K. Y., Aizel, K., Kosasih, C. C., Zlatic, C. O., … Griffin, M. D. W. (2023). Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-42754-w

Readers over time

‘22‘23‘24‘2506121824

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 6

46%

Professor / Associate Prof. 3

23%

Researcher 3

23%

Lecturer / Post doc 1

8%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 12

71%

Pharmacology, Toxicology and Pharmaceut... 2

12%

Sports and Recreations 2

12%

Agricultural and Biological Sciences 1

6%

Save time finding and organizing research with Mendeley

Sign up for free
0