| Abstract: | ["The physiological and pharmacological effects of G protein-coupled receptors (GPCRs) depend on their ability to activate specific effector proteins, primarily G proteins and \u03b2-arrestins. Here, using BRET-based biosensors, we determined the contribution of each individual amino acid of the vasopressin V2 receptor (V2R) to signalling through several G protein subtypes and \u03b2-arrestins. We identified clusters of residues that form either a common or several effector-specific allosteric connections, linking the ligand binding to effector activation. We show how mutations in the ligand binding pocket, the core region, or the effector interaction sites can bias the receptor towards specific signalling pathways. Our data suggest the existence of signalling-specific \u2018micro-conformations\u2019, which are unique for each activated effector. These microstates provide insights into the molecular basis of functional selectivity and biased signalling of G protein-coupled receptors and outline the path to rational engineering of biased therapeutic drugs."] |
