Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor

G‐protein‐coupled receptor (GPCR) ligands impart differing degrees of signaling in the G‐protein and arrestin pathways, in phenomena called “biased signaling”. However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrestin are available. In this study, we observed the NMR signals from methionine residues of the μ‐opioid receptor (μOR) in the balanced‐ and biased‐ligand‐bound states. We found that the intracellular cavity of μOR exists in an equilibrium between closed and multiple open conformations with coupled conformational changes on the transmembrane helices 3, 5, 6, and 7, and that the population of each open conformation determines the G‐protein‐ and arrestin‐mediated signaling levels in each ligand‐bound state. These findings provide insight into the biased signaling of GPCRs and will be helpful for development of analgesics that stimulate μOR with reduced tolerance and dependence. Ein offener und geschlossener Fall: Die NMR‐Analyse ligandgebundener Zustände des μ‐Opioid‐Rezeptors ergab, dass die intrazelluläre Kavität des Rezeptors im Gleichgewicht zwischen geschlossenen und mehreren offenen Konformationen vorliegt und die Population jeder offenen Konformation die vom G‐Protein und vom β‐Arrestin vermittelten Signaltransduktionsniveaus bestimmt. Die Befunde geben Einblick in die Signaltransduktion der G‐Protein‐gekoppelten Rezeptoren.