Building 3D models of ion channels for drug discovery

Understanding potent small-molecule inhibition of TRPC1/4/5 channels

Ion channels are transporters that allow substances in and out of cells. Ion channels formed of TRPC1, TRPC4 and TRPC5 proteins are involved in several heart and circulatory diseases. It is very important to understand, in enough detail, the structure of these proteins and how they open/close to be able to design drugs that will target their activity. Recently, Dr Bon and his team have found molecules called xanthines that are powerful and specific blockers of TRPC1/4/5 ion channels. In this project, they plan to study the interaction between these molecules with the ion channel in intricate details. They will use a variety of methods, including seeing how mutations in the ion channels affects the interaction with xanthines. They can then use the information gained in the lab to build a 3D model of the ion channels with the xanthines attached. This will help them identify the components that are most important for the function of the ion channels, which in turn will help with the design of drugs to work against them. So far, no structures have been determined of TRPC1/4/5 channels interacting with chemical substances. This project will provide the first detailed insights into the requirements for opening and closing of these important drug targets in heart and circulatory disease.