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TitleGlycine receptor mechanism elucidated by electron cryo-microscopy.
Journal, issue, pagesNature, Vol. 526, Issue 7572, Page 224-229, Year 2015
Publish dateOct 8, 2015
AuthorsJuan Du / Wei Lü / Shenping Wu / Yifan Cheng / Eric Gouaux /
PubMed AbstractThe 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.
External linksNature / PubMed:26344198 / PubMed Central
MethodsEM (single particle)
Resolution3.8 - 3.9 Å
Structure data

EMDB-6344, PDB-3jad:
Structure of alpha-1 glycine receptor by single particle electron cryo-microscopy, strychnine-bound state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-6345, PDB-3jae:
Structure of alpha-1 glycine receptor by single particle electron cryo-microscopy, glycine-bound state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-6346, PDB-3jaf:
Structure of alpha-1 glycine receptor by single particle electron cryo-microscopy, glycine/ivermectin-bound state
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-SY9:
STRYCHNINE / alkaloid*YM / Strychnine

ChemComp-IVM:
(2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17 / antiparasitic*YM / Ivermectin

Source
  • danio rerio (zebrafish)
KeywordsSIGNALING PROTEIN/ANTAGONIST / cys loop receptor / alpha-1 glycine receptor / strychnine / SIGNALING PROTEIN-ANTAGONIST complex / SIGNALING PROTEIN / glycine / ivermectin

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