Structural Basis of GPCR-Biased Modulation

G protein-coupled receptors (GPCRs) constitute the largest superfamily of membrane receptors in humans and serve as crucial targets for drug development. These receptors engage multiple downstream signaling pathways, including various G-proteins and arrestins, each of which can elicit distinct physiological and pathological responses. Understanding the mechanisms of biased signaling among these pathways is vital for designing more effective drugs with reduced side effects. In this chapter, we summarize the current understanding of how GPCRs selectively couple to different signaling proteins. We delve into the structural insights derived from recent studies, which reveal how ligands can stabilize specific receptor conformations, thereby favoring particular signaling pathways over others. Furthermore, we highlight various biased ligands and their mechanisms of action, emphasizing their therapeutic potential. These findings provide a critical structural foundation for future drug discovery and optimization efforts, paving the way for more targeted and safer pharmacological interventions. Through a deeper comprehension of biased signaling mechanisms, we aim to enhance the efficacy and safety profiles of new therapeutic agents.