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bioRxiv · 10.1101/2023.04.28.538657

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

Zhao, J.·Elgeti, M.·O'Brien, E.·Sar, C.·El Daibani, A.·Heng, J.·Sun, X.·Che, T.·Hubbell, W. L.·Kobilka, B.·Chen, C.
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Abstract

The -opioid receptor (OR) 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 OR 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 {beta}-arrestin-1 with the OR core binding site appears less specific and occurs with much lower affinity than binding of G protein Gi. One-Sentence SummaryLigand-dependent conformational dynamics of the -opioid receptor determine downstream signaling efficacy.

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Zhao, J., Elgeti, M., O'Brien, E., Sar, C., El Daibani, A., Heng, J., Sun, X., Che, T., Hubbell, W. L., Kobilka, B., Chen, C.. 2023-04-29. Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy. https://doi.org/10.1101/2023.04.28.538657

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