(366a) A Combinatory Multi-Technique Approach to Advance GPCR Pharmacology

G protein-coupled receptors (GPCRs) are a superfamily of over 800 integral membrane proteins that are a major target of modern drug therapies. A GPCR ligand’s ability to elicit a specific downstream response is termed its ‘efficacy’, and the ligand’s direct effect on the structure and activity of the receptor is termed its ‘molecular efficacy’. Furthermore, ligands can bias the downstream signaling of their target receptors, a concept termed ‘functional selectivity’. Both the molecular efficacy and functional selectivity of the ligand dictates all subsequent downstream signaling cascades and eventual physiological response. The emergence of numerous high-resolution structures for GPCRs has energized structure-based drug discovery efforts to design potent, selective ligands that modulate pathological signaling. Nonetheless, a significant limitation to characterize the structural and biochemical basis of GPCR signaling, molecular efficacy, and functional selectivity are the technical limitations that prevent quantitative studies in a high-throughput manner. The objective of my studies have been focused towards advancing GPCR pharmacology by overcoming these limitations through the combinatorial use of multiple protein engineering and expression techniques, and developing novel therapeutic tools and assays to address the current needs in GPCR pharmacology.