Ligand efficacy modulates conformational dynamics of the µ-opioid receptor

Zhao, Jiawei and Elgeti, Matthias and O'Brien, Evan and Sár, Cecília and Daibani, Amal El and Heng, Jie and Sun, Xiaoou and Whie, Elizabeth and Che, Tao and Hubbell, Wayne and Kobilka, Brian and Chen, Chunlai (2024) Ligand efficacy modulates conformational dynamics of the µ-opioid receptor. NATURE. ISSN 0028-0836

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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.

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