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Structure paper

TitleStructure of a human synaptic GABA receptor.
Journal, issue, pagesNature, Vol. 559, Issue 7712, Page 67-72, Year 2018
Publish dateJun 27, 2018
AuthorsShaotong Zhu / Colleen M Noviello / Jinfeng Teng / Richard M Walsh / Jeong Joo Kim / Ryan E Hibbs /
PubMed AbstractFast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). ...Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.
External linksNature / PubMed:29950725 / PubMed Central
MethodsEM (single particle)
Resolution3.86 - 3.92 Å
Structure data

7816

6d6t

EMDB-7816, PDB-6d6t:
Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation B
Method: EM (single particle) / Resolution: 3.86 Å

7817

6d6u

EMDB-7817, PDB-6d6u:
Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation A
Method: EM (single particle) / Resolution: 3.92 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM / Γ-Aminobutyric acid

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-FYP:
ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / antagonist*YM / Flumazenil

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Ligand-gated ion channel / GABA-A receptor / Cys-loop receptor

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