Grant: Project Grant

40% of pharmaceuticals target G protein-coupled receptors (GPCRs), a class of membrane proteins which regulate vision, sensory- and neurotransmitter-mediated response, inflammation, and signalling across cell membranes. GPCRs are often imagined as molecular switches whose intracellular topology is primed for activation upon binding of a ligand to an extracellular drug pocket. The adenosine A2A receptor (A2AR) is a prototypical GPCR and one of the most important drug targets in inflammation, cancer, sickle cell disease, diabetes, and brain disorders such as Parkinson's disease. Activation mechanisms and drug response of A2AR can be understood using a spectroscopic technique called NMR which allows us to "visualize" inactive states, intermediates, and specific active states all at once. Thus, the effect of a new drug or lead compound can be immediately understood in terms of the distribution of states that result and are seen by NMR. We also present new ways of studying GPCR activation by NMR of either the ligand, the receptor, allosteric species such as metals, or the G protein binding protein. Armed with this new methodology we plan to advance our understanding of many nuances of A2AR activation and add to our arsenal of drug discovery methods in this important Parkinson's target.