Structure of a human synaptic GABAA receptor.

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Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE

Structure of a human synaptic GABAA receptor.

Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27.

PubMed ID

29950725 [ View in PubMed

]

Abstract

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (gamma-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA 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 alpha1beta2gamma2 GABAA 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.

DrugBank Data that Cites this Article

Drugs

Oxazepam

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
1,2-Benzodiazepine	GABA(A) Receptor (Protein Group)	Protein group	Humans	Unknown	Positive allosteric modulator	Details
1,2-Benzodiazepine	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Unknown	Ligand	Details
Adinazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Adinazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Alprazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Alprazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Bentazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Bentazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Bromazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Bromazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Brotizolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Brotizolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Camazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Camazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Chlordiazepoxide	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Chlordiazepoxide	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Cinazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Cinazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Cinolazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Cinolazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Clobazam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Clonazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Clorazepic acid	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Clorazepic acid	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Clotiazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Clotiazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Cloxazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Cloxazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Delorazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Delorazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Diazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Diazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Doxefazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Doxefazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Estazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Estazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Ethyl loflazepate	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Ethyl loflazepate	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Etizolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Etizolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Flunitrazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Flunitrazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Flurazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Flurazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Halazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Halazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Unknown	Ligand	Details
Ketazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Ketazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Loprazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Loprazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Unknown	Ligand	Details
Lorazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Lorazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Lormetazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Lormetazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Medazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Medazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Mexazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Midazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Midazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Nitrazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Nitrazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Nordazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Nordazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Oxazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Oxazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Oxazepam acetate	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Oxazepam acetate	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Pinazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Pinazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Prazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Prazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Quazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Quazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Remimazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Remimazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details
Temazepam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Temazepam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Unknown	Ligand	Details
Triazolam	GABA(A) Receptor (Protein Group)	Protein group	Humans	Yes	Positive allosteric modulator	Details
Triazolam	GABA(A) Receptor Benzodiazepine Binding Site (Protein Group)	Protein group	Humans	Yes	Ligand	Details