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Efficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region

Author

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  • Yutaka Kofuku

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    Japan Biological Informatics Consortium (JBIC))

  • Takumi Ueda

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Junya Okude

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Yutaro Shiraishi

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Keita Kondo

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Masahiro Maeda

    (Shionogi Co., Ltd., Discovery Research Laboratories)

  • Hideki Tsujishita

    (Shionogi Co., Ltd., Discovery Research Laboratories)

  • Ichio Shimada

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST))

Abstract

Many drugs that target G-protein-coupled receptors (GPCRs) induce or inhibit their signal transduction with different strengths, which affect their therapeutic properties. However, the mechanism underlying the differences in the signalling levels is still not clear, although several structures of GPCRs complexed with ligands determined by X-ray crystallography are available. Here we utilized NMR to monitor the signals from the methionine residue at position 82 in neutral antagonist- and partial agonist-bound states of β2-adrenergic receptor (β2AR), which are correlated with the conformational changes of the transmembrane regions upon activation. We show that this residue exists in a conformational equilibrium between the inverse agonist-bound states and the full agonist-bound state, and the population of the latter reflects the signal transduction level in each ligand-bound state. These findings provide insights into the multi-level signalling of β2AR and other GPCRs, including the basal activity, and the mechanism of signal transduction mediated by GPCRs.

Suggested Citation

  • Yutaka Kofuku & Takumi Ueda & Junya Okude & Yutaro Shiraishi & Keita Kondo & Masahiro Maeda & Hideki Tsujishita & Ichio Shimada, 2012. "Efficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2046
    DOI: 10.1038/ncomms2046
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    Cited by:

    1. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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