How Ligands Achieve Biased Signaling toward Arrestins

G protein-coupled receptors (GPCRs) mediate the effects of various endogenous and extracellular stimuli through multiple transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. Biased signaling, which preferentially activates certain G protein or GRK/arrestin signaling pathways, provides great opportunities for developing drugs with enhanced therapeutic efficacy and minimized side effects. In this Review, we review studies addressing the structural dynamics of GPCRs bound to balanced and biased ligands and current consensus on how ligand-receptor interactions determine signaling outcomes. We also examine the conformational changes in GPCRs when in complex with G proteins, arrestins, and GRKs, highlighting a more profound impact of signal transducers on receptor rearrangements compared with biased ligands. This evidence supports the idea that biased signaling can be achieved through the promotion of multiple conformational states by biased agonists and the stabilization of specific active conformations by individual signal transducers.