The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement

J Biol Chem. 2020 Jun 12;295(24):8285-8301. doi: 10.1074/jbc.RA119.012351. Epub 2020 Apr 24.


Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the β-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11-IL-11Rα complex.

Keywords: IL6 family cytokine; cancer; cytokine; fibrosis; gp130; inflammation; interleukin; receptor structure-function; signaling; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Cell Line, Tumor
  • Entropy
  • Humans
  • Interleukin-11 / metabolism*
  • Interleukin-11 Receptor alpha Subunit / chemistry*
  • Interleukin-11 Receptor alpha Subunit / genetics
  • Interleukin-11 Receptor alpha Subunit / metabolism*
  • Models, Molecular
  • Mutation / genetics
  • Protein Binding
  • Protein Domains
  • Structure-Activity Relationship
  • Thermodynamics


  • IL11 protein, human
  • Interleukin-11
  • Interleukin-11 Receptor alpha Subunit