Recent developments in biased agonism

The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an “active” conformation. In the past decade, however, it has been appreciated that ligands can induce distinct “active” receptor conformations with unique downstream functional signaling profiles. Building on the initial recognition of the existence of such “biased ligands”, recent years have witnessed significant developments in several areas of GPCR biology. These include increased understanding of structural and biophysical mechanisms underlying biased agonism, improvements in characterization and quantification of ligand efficacy, as well as clinical development of these novel ligands. Here we review recent major developments in these areas over the past several years.