Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy.

ABSTRACT: The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance (DEER) and single-molecule fluorescence resonance energy transfer (smFRET), how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several cytoplasmic receptor conformations interconverting on different timescales, including a pre-activated receptor conformation which is capable of G protein binding, and a fully activated conformation which dramatically lowers GDP affinity within the ternary complex. Interaction of β-arrestin-1 with the μOR core binding site appears less specif

SUBMITTER: Zhao J 

PROVIDER: S-EPMC10168371 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature