Leveraging structure and function studies of thromboxane A2 receptors for drugs targeting cardiovascular and inflammatory diseases

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This proposal outlines a multifaceted approach to solving the atomic resolution structure of the thromboxane A2 prostanoid (TP) receptor in complex with a potential drug candidate using X-ray crystallography to inform the development of drugs targeting cardiovascular and inflammatory diseases. TP receptors are medically important G protein-coupled receptors (GPCRs) that are activated by the endogenous prostanoid thromboxane A2 (TXA). The TXA-TP receptor transmembrane signaling system has been implicated in a range of cardiovascular as well as inflammatory and proliferatory conditions, like asthma and Alzheimer's disease and certain cancers, making it an attractive target for the development of therapeutics. In the absence of a high-resolution structure, however, the TP receptor has remained an elusive drug target. A structural understanding of the molecular basis underlying TP function and ligand-recognition will not only inform the rational design of drugs inhibiting TP receptors, it will also serve as a molecular blueprint for the eight cognate prostanoid receptor subtypes that are increasingly recognized as targets for therapeutic drug development. This project will therefore open avenues for the structure-based design of inhibitors targeting TP receptors and the wider prostanoid system. The methodological approach to achieving this aim comprises state-of-the-art protein expression and purification techniques, supported by protein engineering and thorough biochemical characterization of the TP receptor constructs. This will ensure the production of high-quality protein in quantities suitable for crystallization trials. The full range of traditional and innovative approaches for crystallizing membrane proteins will be tested to solve the co-crystal structure of the TP receptor in complex with a potential drug candidate. Collectively, this project bridges the disciplines of biochemistry, structural biology and medicinal chemistry. It will be hosted by Professor Martin Caffrey at Trinity College Dublin (one of the foremost scientists in the field of membrane protein structural biology) and will be undertaken in collaboration with a multidisciplinary team of international experts, including Professor Brian Kobilka of Stanford University (2012 winner of the Nobel Prize for Chemistry for his research on GPCRs) and Professor B. Therese Kinsella of University College Dublin (thromboxane A2 receptor pharmacologist and Chief Scientific Officer of ATXA Therapeutics Ltd., a company dedicated to the development of drugs targeting TP receptors). Each member will provide specialized advice and a resourceful environment to support the accomplishment of the Applicant's research program goals and overall professional development.