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Glycine receptor mechanism elucidated by electron cryo-microscopy

Author

Listed:
  • Juan Du

    (Vollum Institute, Oregon Health & Science University)

  • Wei Lü

    (Vollum Institute, Oregon Health & Science University)

  • Shenping Wu

    (University of California San Francisco)

  • Yifan Cheng

    (University of California San Francisco)

  • Eric Gouaux

    (Vollum Institute, Oregon Health & Science University
    Howard Hughes Medical Institute, Oregon Health & Science University)

Abstract

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:526:y:2015:i:7572:d:10.1038_nature14853
    DOI: 10.1038/nature14853
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    Cited by:

    1. 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.
    2. Xiaofen Liu & Weiwei Wang, 2023. "Asymmetric gating of a human hetero-pentameric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. 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.
    4. 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.

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