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Structural basis of GABAB receptor–Gi protein coupling

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  • Cangsong Shen

    (Huazhong University of Science and Technology (HUST)
    Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Chunyou Mao

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Chanjuan Xu

    (Huazhong University of Science and Technology (HUST)
    Guangzhou Regenerative Medicine and Health Guangdong Laboratory)

  • Nan Jin

    (Huazhong University of Science and Technology (HUST)
    Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Huibing Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Qingya Shen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Xiaomei Wang

    (Huazhong University of Science and Technology (HUST))

  • Tingjun Hou

    (Zhejiang University)

  • Zhong Chen

    (Zhejiang Chinese Medical University)

  • Philippe Rondard

    (Université de Montpellier, CNRS, INSERM)

  • Jean-Philippe Pin

    (Université de Montpellier, CNRS, INSERM)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases
    Zhejiang University School of Medicine)

  • Jianfeng Liu

    (Huazhong University of Science and Technology (HUST)
    Guangzhou Regenerative Medicine and Health Guangdong Laboratory)

Abstract

G-protein-coupled receptors (GPCRs) have central roles in intercellular communication1,2. Structural studies have revealed how GPCRs can activate G proteins. However, whether this mechanism is conserved among all classes of GPCR remains unknown. Here we report the structure of the class-C heterodimeric GABAB receptor, which is activated by the inhibitory transmitter GABA, in its active form complexed with Gi1 protein. We found that a single G protein interacts with the GB2 subunit of the GABAB receptor at a site that mainly involves intracellular loop 2 on the side of the transmembrane domain. This is in contrast to the G protein binding in a central cavity, as has been observed with other classes of GPCR. This binding mode results from the active form of the transmembrane domain of this GABAB receptor being different from that of other GPCRs, as it shows no outside movement of transmembrane helix 6. Our work also provides details of the inter- and intra-subunit changes that link agonist binding to G-protein activation in this heterodimeric complex.

Suggested Citation

  • Cangsong Shen & Chunyou Mao & Chanjuan Xu & Nan Jin & Huibing Zhang & Dan-Dan Shen & Qingya Shen & Xiaomei Wang & Tingjun Hou & Zhong Chen & Philippe Rondard & Jean-Philippe Pin & Yan Zhang & Jianfeng, 2021. "Structural basis of GABAB receptor–Gi protein coupling," Nature, Nature, vol. 594(7864), pages 594-598, June.
    • Handle: RePEc:nat:nature:v:594:y:2021:i:7864:d:10.1038_s41586-021-03507-1
    DOI: 10.1038/s41586-021-03507-1
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    Cited by:

    1. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021. "Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Marie-Lise Jobin & Sana Siddig & Zsombor Koszegi & Yann Lanoiselée & Vladimir Khayenko & Titiwat Sungkaworn & Christian Werner & Kerstin Seier & Christin Misigaiski & Giovanna Mantovani & Markus Sauer, 2023. "Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Moon Young Yang & Soo-Kyung Kim & William A. Goddard, 2022. "G protein coupling and activation of the metabotropic GABAB heterodimer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    6. Chanjuan Xu & Yiwei Zhou & Yuxuan Liu & Li Lin & Peng Liu & Xiaomei Wang & Zhengyuan Xu & Jean-Philippe Pin & Philippe Rondard & Jianfeng Liu, 2024. "Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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