Structural insights into small molecule activation of TRPC4/5 channels

点击翻译按钮获取中文摘要

The cell is the basic unit of all known living organisms, and humans consist of many different types of cells, the majority of which are highly specialised. In order to function properly, cells need to communicate with their environment and with neighbouring cells. This requires the transmission of information across the cell membrane, which separates the cellular content from the extracellular environment. One major mechanism of communication is the movement across cell membranes of ions - mainly sodium, potassium, calcium and chloride - through channel-forming proteins that are located within the membrane, so-called ion channels. Many human diseases result from abnormalities in the function of ion channels, and many successful therapeutic drugs work by activating or blocking ion channels. Our research focuses on ion channels called TRPC4 and TRPC5 channels, which are increasingly recognised as potential drug targets in a variety of diseases - including cancer, heart failure, cardiovascular and metabolic disease, epilepsy and anxiety disorders - but for which the development of activators and blockers as drugs has proven difficult. For example, we previously discovered that Englerin A, a natural product isolated from an African tree used in traditional medicine, selectively kills renal cancer cells by the potent activation of TRPC4 channels. Englerin A is also a very potent activator of TRPC5 channels. However, Englerin A is too unstable and too toxic to be used as an anti-cancer drug. In this project, we will study how Englerin A interacts with TRPC4 and TRPC5 channels . We will use a combination of experimental approaches, building on the specific expertise of the different team members. For example, we will use analogues of Englerin A that can chemically react with TRPC4/5 channels, and use mass spectrometry to identify where in the channels the reactions take place. In addition, we will use state-of-the-art electron microscopes - part of a recent £17m investment by the University of Leeds and the Wellcome Trust - to determine the three-dimensional structures of TRPC4/5 channels and their complexes with Englerin A.These results will reveal how Englerin A works on the molecular level, and how the activity of TRPC4/5 channels can be regulated by small molecules. This will enable future development of drugs that targets specific TRPC4 or TRPC5 channels, which may lead to the development of the first drugs that target these channels. We will ensure the future use of our results in the drug discovery process through our ongoing collaboration with the Lead Discovery Center of the Max Planck Society, with the aim to develop drug-like molecules for clinical trials. In addition, we will publish our results in open access publications, and make our data and materials freely available through public repositories.