Project 461786

The G Protein-Coupled Receptor (GPCR) superfamily consists of over 830 distinct 7-transmembrane proteins, governing sensory and neuronal signalling, cell homeostasis, and immune response. As one third of all approved pharmaceuticals target GPCRs, a deep understanding of their mechanism of action is critical to understanding cell signaling and advancing drug discovery strategies. This project focuses on aspects of signalling associated with a specific GPCR called the adenosine A2A receptor (A2AR), which is found in the cardiovascular, immune, respiratory, renal and central nervous systems. A2AR activation mediates sleep, angiogenesis, and immunosuppression, while specific agonists and antagonists have been clinically tested to treat inflammation, cancer, pain, and neurodegenerative diseases. Using mutagenesis, biophysical studies, and Nuclear Magnetic Resonance (NMR), we will study A2AR conformational dynamics in response to drug, to understand GPCR signalling at a molecular level - specifically addressing questions of energetics, and pharmacology. Building on these insights, we will then develop a "next-generation" approach to drug discovery using in-house technology to discover sub-type selective bivalent drugs and drug-antibody conjugates, using A2AR as a test system for GPCR drug discovery. The studies allow us to better understand receptor activation and signalling and the connection to pharmacology, while utilizing this knowledge toward the discovery of next-generation bivalent drugs and antibodies.