Ligand efficacy modulates conformational dynamics of the µ-opioid receptor

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 () and Chunlai Chen ()
Additional contact information
Jiawei Zhao: Tsinghua University
Matthias Elgeti: University of California, Los Angeles
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
Xiaoou Sun: 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

Nature, 2024, vol. 629, issue 8011, 474-480

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07295-2

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