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Structure of human GABAB receptor in an inactive state

Author

Listed:
  • Jinseo Park

    (Columbia University)

  • Ziao Fu

    (Columbia University)

  • Aurel Frangaj

    (Columbia University)

  • Jonathan Liu

    (Columbia University)

  • Lidia Mosyak

    (Columbia University)

  • Tong Shen

    (University of California Davis)

  • Vesna N. Slavkovich

    (Columbia University)

  • Kimberly M. Ray

    (Columbia University)

  • Jaume Taura

    (Icahn School of Medicine at Mount Sinai)

  • Baohua Cao

    (Columbia University)

  • Yong Geng

    (Columbia University
    Chinese Academy of Sciences)

  • Hao Zuo

    (Columbia University)

  • Yongjun Kou

    (Chinese Academy of Sciences)

  • Robert Grassucci

    (Columbia University)

  • Shaoxia Chen

    (MRC Laboratory of Molecular Biology)

  • Zheng Liu

    (Columbia University)

  • Xin Lin

    (Columbia University
    New York State Psychiatric Institute)

  • Justin P. Williams

    (Columbia University)

  • William J. Rice

    (New York Structural Biology Center)

  • Edward T. Eng

    (New York Structural Biology Center)

  • Rick K. Huang

    (Howard Hughes Medical Institute)

  • Rajesh K. Soni

    (Columbia University)

  • Brian Kloss

    (New York Structural Biology Center)

  • Zhiheng Yu

    (Howard Hughes Medical Institute)

  • Jonathan A. Javitch

    (Columbia University
    Columbia University
    New York State Psychiatric Institute
    Columbia University)

  • Wayne A. Hendrickson

    (Columbia University
    Columbia University
    New York Structural Biology Center)

  • Paul A. Slesinger

    (Icahn School of Medicine at Mount Sinai)

  • Matthias Quick

    (Columbia University
    New York State Psychiatric Institute)

  • Joseph Graziano

    (Columbia University)

  • Hongtao Yu

    (University of Texas Southwestern Medical Center)

  • Oliver Fiehn

    (University of California Davis)

  • Oliver B. Clarke

    (Columbia University
    Columbia University)

  • Joachim Frank

    (Columbia University
    Columbia University)

  • Qing R. Fan

    (Columbia University
    Columbia University)

Abstract

The human GABAB receptor—a member of the class C family of G-protein-coupled receptors (GPCRs)—mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2–6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9–14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique ‘intersubunit latch’ within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Suggested Citation

  • Jinseo Park & Ziao Fu & Aurel Frangaj & Jonathan Liu & Lidia Mosyak & Tong Shen & Vesna N. Slavkovich & Kimberly M. Ray & Jaume Taura & Baohua Cao & Yong Geng & Hao Zuo & Yongjun Kou & Robert Grassucc, 2020. "Structure of human GABAB receptor in an inactive state," Nature, Nature, vol. 584(7820), pages 304-309, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7820:d:10.1038_s41586-020-2452-0
    DOI: 10.1038/s41586-020-2452-0
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    Citations

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    Cited by:

    1. 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.
    2. Yaejin Yun & Hyeongseop Jeong & Thibaut Laboute & Kirill A. Martemyanov & Hyung Ho Lee, 2024. "Cryo-EM structure of human class C orphan GPCR GPR179 involved in visual processing," Nature Communications, Nature, vol. 15(1), pages 1-13, 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. 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.
    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.
    7. 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.
    8. Xin Lin & Davide Provasi & Colleen M. Niswender & Wesley B. Asher & Jonathan A. Javitch, 2024. "Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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