Cytokines are small protein messengers that transmit information from the outside of the cell to the inside of the cell. They are important regulators of the immune system, and when these messangers misfire, it can result in inflammatory disease, autoimmunity or cancer. Our research is focused on determining what these molecules look like, how they function, and how the signals they send are regulated.
We generate detailed 3D “pictures” of these molecules, and the molecules they interact with. We use this information to understand how they work, what is going wrong in a disease setting, and to try to design drugs to change how they function.
To aid the design of new medicines through understanding what protein molecules look like at atomic resolution.
We have made significant contributions to understanding how cytokine signalling is regulated. Our structural studies are being used to enable drug discovery projects aimed at making new treatments for cancer.
The cytokine Thrombopoietin (Tpo) controls the maintenance of blood stem cells as well as the numbers of platelet in the blood. Clinically, excessive signalling through the molecule that recognises Tpo (the Thrombopoietin Receptor) causes a type of blood cancer called myeloproliferative disease.
The architecture of TpoR is distinct from any other cytokine receptor and there is a complete lack of structural data for it. We have developed a recombinant expression system for Tpo and TpoR, which interact readily and we are using crystallography and CryoEM to solve the structure of the TpoR:TpoR complex. We are also using our unique reagents and structural information to developing novel strategies for inhibiting excessive TpoR signalling, with the aim of generating new treatments for myeloproliferative disease. This work is in collaboration with the Babon Lab (WEHI).
The Suppressors of Cytokine Signalling (SOCS) have long been studied at WEHI for their role in negative regulation of cytokine signalling. The Kershaw and Babon Labs have made a significant contribution to basic research in this area, solving the first structures of SOCS1 as the first structures of SOCS1 and SOCS3 bound to the JAK kinase domain. More recently, with the advent of immunotherapy as an exciting treatment option for cancer, inhibiting the SOCS proteins provides a possible route to boost the efficacy of current immunotherapy approaches. We are studying the mechanism of SOCS proteins and other negative regulators of cytokine signaling such as LNK and PTP1B. This work is in collaboration with the Babon Lab (WEHI).
T cells are a critical part of a healthy immune system, and T-cell activation is one of several key events required to successfully mount an immune response. Soluble CTLA4 proteins block T cell activation, and are already in use as therapeutics for rheumatoid arthritis and organ transplant rejection (e.g Abatacept), but recent publications from several groups indicate the mode of action of current CTLA4-based therapeutics may be more complex that initially thought.
We are exploring novel CTLA4-fusions and their potential as immunomodulatory therapeutics. This project involves rational design of CTLA4 variants with altered immunomodulatory activity, and structural studies on the mode of binding with target proteins, to allow further refinement as therapeutics as well as elucidation of the mode of action. This work is in collaboration with Associate Professor Ross Dickins (Monash).
Project resource: Monash University research project: Novel immunosuppressive mechanisms of CTLA4 and CTLA4-Ig therapies