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Ligand efficacy modulates conformational dynamics of the µ-opioid receptor

Author

Listed:
  • Jiawei Zhao

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Matthias Elgeti

    (University of California, Los Angeles
    University of Leipzig Medical Center)

  • Evan S. O’Brien

    (Stanford University School of Medicine)

  • Cecília P. Sár

    (University of Pécs)

  • Amal EI Daibani

    (Washington University School of Medicine)

  • Jie Heng

    (Tsinghua University
    Tsinghua University)

  • Xiaoou Sun

    (Tsinghua University
    Tsinghua University)

  • Elizabeth White

    (Stanford University School of Medicine)

  • Tao Che

    (Washington University School of Medicine)

  • Wayne L. Hubbell

    (University of California, Los Angeles)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Chunlai Chen

    (Tsinghua University
    Tsinghua University)

Abstract

The µ-opioid receptor (µOR) is an important target for pain management1 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 Gi.

Suggested Citation

  • Jiawei Zhao & Matthias Elgeti & Evan S. O’Brien & Cecília P. Sár & Amal EI Daibani & Jie Heng & Xiaoou Sun & Elizabeth White & Tao Che & Wayne L. Hubbell & Brian K. Kobilka & Chunlai Chen, 2024. "Ligand efficacy modulates conformational dynamics of the µ-opioid receptor," Nature, Nature, vol. 629(8011), pages 474-480, May.
    • Handle: RePEc:nat:nature:v:629:y:2024:i:8011:d:10.1038_s41586-024-07295-2
    DOI: 10.1038/s41586-024-07295-2
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