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

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