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Conformational transitions and allosteric modulation in a heteromeric glycine receptor

Author

Listed:
  • Eric Gibbs

    (Case Western Reserve University)

  • Emily Klemm

    (Case Western Reserve University)

  • David Seiferth

    (University of Oxford)

  • Arvind Kumar

    (Case Western Reserve University)

  • Serban L. Ilca

    (New York Structural Biology Center
    Simons Electron Microscopy Center)

  • Philip C. Biggin

    (University of Oxford)

  • Sudha Chakrapani

    (Case Western Reserve University
    Case Western Reserve University)

Abstract

Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βBGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of α1βGlyR and provide a framework for further study of this physiologically important channel.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37106-7
    DOI: 10.1038/s41467-023-37106-7
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    References listed on IDEAS

    as
    1. Marc Gielen & Philip Thomas & Trevor G. Smart, 2015. "The desensitization gate of inhibitory Cys-loop receptors," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Ryan E. Hibbs & Eric Gouaux, 2011. "Principles of activation and permeation in an anion-selective Cys-loop receptor," Nature, Nature, vol. 474(7349), pages 54-60, June.
    4. Serban L. Ilca & Xiaoyu Sun & Kamel El Omari & Abhay Kotecha & Felix Haas & Frank DiMaio & Jonathan M. Grimes & David I. Stuart & Minna M. Poranen & Juha T. Huiskonen, 2019. "Multiple liquid crystalline geometries of highly compacted nucleic acid in a dsRNA virus," Nature, Nature, vol. 570(7760), pages 252-256, June.
    5. 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.
    6. Ghérici Hassaine & Cédric Deluz & Luigino Grasso & Romain Wyss & Menno B. Tol & Ruud Hovius & Alexandra Graff & Henning Stahlberg & Takashi Tomizaki & Aline Desmyter & Christophe Moreau & Xiao-Dan Li , 2014. "X-ray structure of the mouse serotonin 5-HT3 receptor," Nature, Nature, vol. 512(7514), pages 276-281, August.
    7. Xin Huang & Hao Chen & Klaus Michelsen & Stephen Schneider & Paul L. Shaffer, 2015. "Crystal structure of human glycine receptor-α3 bound to antagonist strychnine," Nature, Nature, vol. 526(7572), pages 277-280, October.
    8. Sandip Basak & Yvonne Gicheru & Shanlin Rao & Mark S. P. Sansom & Sudha Chakrapani, 2018. "Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor," Nature, Nature, vol. 563(7730), pages 270-274, November.
    9. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    10. Juan Du & Wei Lü & Shenping Wu & Yifan Cheng & Eric Gouaux, 2015. "Glycine receptor mechanism elucidated by electron cryo-microscopy," Nature, Nature, vol. 526(7572), pages 224-229, October.
    11. Stephen P. Kelley & James I. Dunlop & Ewen F. Kirkness & Jeremy J. Lambert & John A. Peters, 2003. "A cytoplasmic region determines single-channel conductance in 5-HT3 receptors," Nature, Nature, vol. 424(6946), pages 321-324, July.
    12. Hongtao Zhu & Eric Gouaux, 2021. "Architecture and assembly mechanism of native glycine receptors," Nature, Nature, vol. 599(7885), pages 513-517, November.
    13. Atsuo Miyazawa & Yoshinori Fujiyoshi & Nigel Unwin, 2003. "Structure and gating mechanism of the acetylcholine receptor pore," Nature, Nature, vol. 423(6943), pages 949-955, June.
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