Ligand efficacy modulates conformational dynamics of the µ-opioid receptor

• Published in: Nature (London) Vol. 629; no. 8011; pp. 474 - 480
• Main Authors: Zhao, Jiawei, Elgeti, Matthias, O'Brien, Evan S, Sár, Cecília P, Ei Daibani, Amal, Heng, Jie, Sun, Xiaoou, White, Elizabeth, Che, Tao, Hubbell, Wayne L, Kobilka, Brian K, Chen, Chunlai
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.05.2024; Nature Publishing Group UK
• Subjects: Affinity; Animals; Arrestin; beta-Arrestins - chemistry; beta-Arrestins - metabolism; Bias; Binding Sites; Drug development; Energy transfer; Fluorescence Resonance Energy Transfer; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - metabolism; Humans; Ligands; Models, Molecular; Morphine; Narcotics; Opioid receptors; Protein Binding; Protein Conformation; Proteins; Receptors; Receptors, Opioid, mu - chemistry; Receptors, Opioid, mu - metabolism; Resonance; Single Molecule Imaging
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07295-2

The µ-opioid receptor (µOR) is an important target for pain management and molecular understanding of drug action on µOR 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 µOR 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 β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of G .