The cytokine interleukin (IL) 11 has been shown to have roles in several cancers, including colon and gastrointestinal cancer. IL-11 signaling has been shown to be a therapeutic target in these diseases. Despite this, the structure of IL-11 and the signaling complexes it forms, is relatively understudied. Our laboratory has solved the first crystal structure of IL-11, and we aim to better understand the formation of the IL-11 signaling complex. We have recently shown that IL-11, like IL-6, forms a hexameric signaling complex with two copies each of IL-11, the IL-11-specific receptor, IL-11Rα and the shared receptor gp130, and that this complex forms in a cooperative manner.
In addition, an antagonistic mutant of IL-11 has been developed, IL-11 Mutein. We have shown, using both analytical ultracentrifugation (AUC) and small-angle X-ray scattering (SAXS), that IL-11 Mutein functions by disrupting the formation of the IL-11 signaling complex, preventing the assembly of the active hexameric signaling complex, thus inhibiting IL-11 signaling. We have solved the crystal structure of IL-11 Mutein. The structure shows that the mutations in IL-11 Mutein markedly alter the conformation of a functional loop, suggesting that the structural dynamics of IL-11 Mutein are key to the mechanism of antagonism. To investigate this, we are currently undertaking solution nuclear magnetic resonance (NMR) experiments, to probe and compare the structural dynamics of IL-11 and IL-11 Mutein. We hope to compliment these experiments with molecular-dynamics simulations in the near future. This work will aid in the design of improved IL-11 Mutein variants and novel IL-11 signaling antagonists that may provide new therapeutic options in cancers and other diseases.