Oral Presentation The 45th Lorne Conference on Protein Structure and Function 2020

The structure of the interleukin-11 signalling complex guides therapeutic design (#41)

Riley D Metcalfe 1 , Eric Hanssen 1 2 , Kaheina Aizel 1 , Andrew P Leis 2 , Courtney O Zlatic 1 , Paul R Gooley 1 , Tracy L Putoczki 3 4 5 , Michael D. W Griffin 1
  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
  2. Advanced Microscopy Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
  3. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  4. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  5. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkvile, Victoria, Australia

The cytokine interleukin (IL)-11 is a therapeutic target in several diseases, including gastrointestinal cancer and fibrosis of the heart and liver. IL-11 is an IL-6 family cytokine member that signals through a complex consisting of the shared cell-surface receptor glycoprotein (gp) 130 and the IL-11 specific receptor IL-11Rα. Our laboratory has previously solved the structure of IL-11 and the extracellular regions of IL-11Rα, which has provided insights into the mechanism of cytokine engagement by IL-11Rα.

We have solved the 3.5 Å cryoEM structure of the IL-11 signalling complex. The complex is a ~170 kDa hexameric complex consisting of two copies each of IL-11, IL-11Rα and gp130. Our structure allows us to map the interfaces in the complex in detail and reveal mechanistic differences in receptor engagement between IL-11 and other cytokines, particularly in the engagement of the shared receptor gp130. We have complemented our cryoEM complex with extensive biophysical analysis of the complex, to understand solution stoichiometry and the thermodynamic mechanisms underpinning formation of the complex. We have also solved a 3.8 Å structure of the complex using X-ray crystallography, which provides complementary insights to the cryoEM structure. The structures of the IL-11 signalling complex allow us to understand the mechanism of action of existing inhibitors targeting IL-11 signalling. This will allow the informed development of novel IL-11 signalling inhibitors, which may be valuable therapeutics. 

Our structure will allow us to better understand the structural mechanisms underpinning IL-11 signalling, which will guide the development and characterisation of new therapeutics.