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Structural basis of the activation of a metabotropic GABA receptor

Author

Listed:
  • Hamidreza Shaye

    (University of Southern California
    University of Southern California)

  • Andrii Ishchenko

    (University of Southern California
    University of Southern California)

  • Jordy Homing Lam

    (University of Southern California
    University of Southern California)

  • Gye Won Han

    (University of Southern California
    University of Southern California)

  • Li Xue

    (Université de Montpellier)

  • Philippe Rondard

    (Université de Montpellier)

  • Jean-Philippe Pin

    (Université de Montpellier)

  • Vsevolod Katritch

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Cornelius Gati

    (Biosciences Division, SLAC National Accelerator Laboratory
    Stanford University)

  • Vadim Cherezov

    (University of Southern California
    University of Southern California
    University of Southern California)

Abstract

Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis1. GABAB belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits2. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1–GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABAB. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.

Suggested Citation

  • Hamidreza Shaye & Andrii Ishchenko & Jordy Homing Lam & Gye Won Han & Li Xue & Philippe Rondard & Jean-Philippe Pin & Vsevolod Katritch & Cornelius Gati & Vadim Cherezov, 2020. "Structural basis of the activation of a metabotropic GABA receptor," Nature, Nature, vol. 584(7820), pages 298-303, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7820:d:10.1038_s41586-020-2408-4
    DOI: 10.1038/s41586-020-2408-4
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    Citations

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    Cited by:

    1. Kento Ojima & Wataru Kakegawa & Tokiwa Yamasaki & Yuta Miura & Masayuki Itoh & Yukiko Michibata & Ryou Kubota & Tomohiro Doura & Eriko Miura & Hiroshi Nonaka & Seiya Mizuno & Satoru Takahashi & Michis, 2022. "Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Janik B. Hedderich & Margherita Persechino & Katharina Becker & Franziska M. Heydenreich & Torben Gutermuth & Michel Bouvier & Moritz Bünemann & Peter Kolb, 2022. "The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. 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.
    4. 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.
    5. Alexa Strauss & Alberto J. Gonzalez-Hernandez & Joon Lee & Nohely Abreu & Purushotham Selvakumar & Leslie Salas-Estrada & Melanie Kristt & Anisul Arefin & Kevin Huynh & Dagan C. Marx & Kristen Gillila, 2024. "Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. 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.
    8. 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.
    9. Michael R. Schamber & Reza Vafabakhsh, 2022. "Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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