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Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family

Author

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  • Hee Ryung Kim

    (School of Pharmacy, Sungkyunkwan University)

  • Jun Xu

    (Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University)

  • Shoji Maeda

    (Stanford University)

  • Nguyen Minh Duc

    (School of Pharmacy, Sungkyunkwan University
    Division of Precision Medicine, Research Institute, National Cancer Center)

  • Donghoon Ahn

    (School of Pharmacy, Sungkyunkwan University)

  • Yang Du

    (School of Life and Health Sciences, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong)

  • Ka Young Chung

    (School of Pharmacy, Sungkyunkwan University)

Abstract

Heterotrimeric G proteins are categorized into four main families based on their function and sequence, Gs, Gi/o, Gq/11, and G12/13. One receptor can couple to more than one G protein subtype, and the coupling efficiency varies depending on the GPCR-G protein pair. However, the precise mechanism underlying different coupling efficiencies is unknown. Here, we study the structural mechanism underlying primary and secondary Gi/o coupling, using the muscarinic acetylcholine receptor type 2 (M2R) as the primary Gi/o-coupling receptor and the β2-adrenergic receptor (β2AR, which primarily couples to Gs) as the secondary Gi/o-coupling receptor. Hydrogen/deuterium exchange mass spectrometry and mutagenesis studies reveal that the engagement of the distal C-terminus of Gαi/o with the receptor differentiates primary and secondary Gi/o couplings. This study suggests that the conserved hydrophobic residue within the intracellular loop 2 of the receptor (residue 34.51) is not critical for primary Gi/o-coupling; however, it might be important for secondary Gi/o-coupling.

Suggested Citation

  • Hee Ryung Kim & Jun Xu & Shoji Maeda & Nguyen Minh Duc & Donghoon Ahn & Yang Du & Ka Young Chung, 2020. "Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16975-2
    DOI: 10.1038/s41467-020-16975-2
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    Cited by:

    1. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. 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.
    3. Sathvik Anantakrishnan & Athi N. Naganathan, 2023. "Thermodynamic architecture and conformational plasticity of GPCRs," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Marin Matic & Pasquale Miglionico & Manae Tatsumi & Asuka Inoue & Francesco Raimondi, 2023. "GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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