National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
5R01GM108921-05
United States
American Heart Association
20POST35210394
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
1R01GM131216-01
United States
Citation
Journal: Nature / Year: 2015 Title: Glycine receptor mechanism elucidated by electron cryo-microscopy. Authors: Juan Du / Wei Lü / Shenping Wu / Yifan Cheng / Eric Gouaux / 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. ...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.
History
Deposition
Sep 12, 2019
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Header (metadata) release
Feb 5, 2020
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Map release
Jul 29, 2020
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Update
Aug 12, 2020
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Current status
Aug 12, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK IV Details: 3.5 ul of 0.1 mg/ml protein solution was applied on a grid in the Vitrobot MkIV chamber set to 100% RH at 4 degC for 30s and then blotted for 2 s and plunged.
Details
Full length Zebrafish GlyR alpha1 homopentamer reconsituted in Nanodisc
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recording
Film or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 4 / Number real images: 5344 / Average electron dose: 40.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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