Discovering the molecular basis of interleukin-3 signalling

SE Broughton1, TR Hercus2, TL Nero1, U Dhagat1, WL Kan2, SK Cheung Tung Shing1, TP Hughes3, AF Lopez2 and MW Parker1

  1. Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent’s Institute of Medical Research, 9 Princes St, Fitzroy, Victoria, Australia
  2. The Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, South Australia, Australia
  3. SAHMRI, North Terrace, Adelaide SA 5000 Australia PO Box 11060, Adelaide SA 5001

Interleukin-3 (IL-3) is a member of the beta common (βc) family of cytokines that regulate the production and function of cells of the haemopoietic and immune systems. The production of IL-3 promotes the growth and viability of certain leukaemic cells, a likely contributing factor to the development of acute and chronic myeloid leukaemia (AML and CML). IL-3 functions through a heterodimeric receptor composed of the IL-3-specific alpha subunit (IL3Rα) and the βc subunit. IL3Rα is overexpressed on leukaemic stem cells as well as AML and CML blast cells, and correlates clinically with reduced patient survival. Understanding how IL-3 binds to IL3Rα to initiate signalling is key to the development of strategies to therapeutically target the IL-3 receptor complex for treatment of AML and CML. However, little is known about how the IL-3 receptor assembles and signals. We have developed a detailed molecular picture of IL-3 receptor assembly and activation through visualisation of the IL-3 receptor complex by X-ray crystallography, supported by molecular modelling and functional studies. We are using the crystal structure of the βc subunit, and a complex with IL-3 and IL3Rα, to identify small molecule inhibitors of this subunit. We can now report structures of both the IL-3 binary (IL-3:IL3Rα and IL-3 superkine:IL3Rα), and structures of Fabs complexed to both the βc subunit and IL3Rα. This information is critical for the development of innovative therapies such as highly selective monoclonal antibodies and small molecules with unique activities to improve clinical practice.