Ligand efficacy modulates conformational dynamics of the -opioid receptor

The mu-opioid receptor (mu OR) is an important target for pain management 1 and molecular understanding of drug action on mu OR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of mu OR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of beta-arrestin-1 with the mu OR core binding site appears less specific and occurs with much lower affinity than binding of Gi. Studies on the mu-opioid receptor using fluorescent labelling of intracellular residues and energy transfer experiments in the presence of different ligands with or without G-protein binding reveals conformational changes that correlate to ligand efficacy.