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Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs

Author

Listed:
  • Arvind Kumar

    (Case Western Reserve University)

  • Sandip Basak

    (Case Western Reserve University)

  • Shanlin Rao

    (University of Oxford)

  • Yvonne Gicheru

    (Case Western Reserve University)

  • Megan L. Mayer

    (Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University)

  • Mark S. P. Sansom

    (University of Oxford)

  • Sudha Chakrapani

    (Case Western Reserve University
    Case Western Reserve University, Cleveland)

Abstract

Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered. Here, we present Cryo-EM structures of the full-length GlyR protein complex reconstituted into lipid nanodiscs that are captured in the unliganded (closed), glycine-bound (open and desensitized), and allosteric modulator-bound conformations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment.

Suggested Citation

  • Arvind Kumar & Sandip Basak & Shanlin Rao & Yvonne Gicheru & Megan L. Mayer & Mark S. P. Sansom & Sudha Chakrapani, 2020. "Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17364-5
    DOI: 10.1038/s41467-020-17364-5
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    Cited by:

    1. Zhengshan Hu & Xiangdong Zheng & Jian Yang, 2023. "Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Xiaofen Liu & Weiwei Wang, 2023. "Asymmetric gating of a human hetero-pentameric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Vikram Dalal & Mark J. Arcario & John T. Petroff & Brandon K. Tan & Noah M. Dietzen & Michael J. Rau & James A. J. Fitzpatrick & Grace Brannigan & Wayland W. L. Cheng, 2024. "Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    5. Dagimhiwat H. Legesse & Chen Fan & Jinfeng Teng & Yuxuan Zhuang & Rebecca J. Howard & Colleen M. Noviello & Erik Lindahl & Ryan E. Hibbs, 2023. "Structural insights into opposing actions of neurosteroids on GABAA receptors," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Eric Gibbs & Emily Klemm & David Seiferth & Arvind Kumar & Serban L. Ilca & Philip C. Biggin & Sudha Chakrapani, 2023. "Conformational transitions and allosteric modulation in a heteromeric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Grace D. Galles & Daniel T. Infield & Colin J. Clark & Marcus L. Hemshorn & Shivani Manikandan & Frederico Fazan & Ali Rasouli & Emad Tajkhorshid & Jason D. Galpin & Richard B. Cooley & Ryan A. Mehl &, 2023. "Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Xiaolong Gao & Philipp A. M. Schmidpeter & Vladimir Berka & Ryan J. Durham & Chen Fan & Vasanthi Jayaraman & Crina M. Nimigean, 2022. "Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. John T. Petroff & Noah M. Dietzen & Ezry Santiago-McRae & Brett Deng & Maya S. Washington & Lawrence J. Chen & K. Trent Moreland & Zengqin Deng & Michael Rau & James A. J. Fitzpatrick & Peng Yuan & Th, 2022. "Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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