Allosteric coupling and biased agonism in G protein?coupled receptors

G protein-coupled receptors (GPCRs) are essential cell membrane signaling molecules and represent the most important class of drug targets. Some pathways downstream a GPCR may be responsible for adverse effects, while others mediate therapeutic efficacy. Biased ligands preferentially activate only subset all pathways. They hold great potential to become next-generation drugs with less side effects due their exclusively desired However, molecular basis biased agonism is poorly understood. activation occurs through allosteric coupling, propagation conformational changes from extracellular ligand-binding pocket intracellular protein-binding interface. Comparison structures in complex proteins or ?-arrestin reveals that transducer coupling results closure trapping agonist inside its binding site. Allosteric appears transducer-specific offering possibility harnessing this mechanism design ligands. Here, we review biochemical, pharmacological, structural, biophysical evidence delineate should consequence preferential one transducer-binding As leads large structural rearrangements pocket, survey an extended mode interact receptor domains. We propose use ligand-specific triggers relayed specific transducer, eventually leading signaling.