Structure of a human synaptic GABAA receptor.

Article Details

Citation

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
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
1,2-BenzodiazepineGABA(A) Receptor (Protein Group)Protein groupHumans
Unknown
Positive allosteric modulator
Details
1,2-BenzodiazepineGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Unknown
Ligand
Details
AdinazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
AdinazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
AlprazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
AlprazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
BentazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
BentazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
BromazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
BromazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
BrotizolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
BrotizolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
CamazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
CamazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
ChlordiazepoxideGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
ChlordiazepoxideGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
CinazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
CinazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
CinolazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
CinolazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
ClobazamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
ClonazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
Clorazepic acidGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
Clorazepic acidGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
ClotiazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
ClotiazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
CloxazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
CloxazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
DelorazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
DelorazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
DiazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
DiazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
DoxefazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
DoxefazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
EstazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
EstazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
Ethyl loflazepateGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
Ethyl loflazepateGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
EtizolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
EtizolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
FlunitrazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
FlunitrazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
FlurazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
FlurazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
HalazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
HalazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Unknown
Ligand
Details
KetazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
KetazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
LoprazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
LoprazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Unknown
Ligand
Details
LorazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
LorazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
LormetazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
LormetazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
MedazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
MedazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
MexazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
MidazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
MidazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
NitrazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
NitrazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
NordazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
NordazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
OxazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
OxazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
Oxazepam acetateGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
Oxazepam acetateGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
PinazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
PinazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
PrazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
PrazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
QuazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
QuazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
RemimazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
RemimazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details
TemazepamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
TemazepamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Unknown
Ligand
Details
TriazolamGABA(A) Receptor (Protein Group)Protein groupHumans
Yes
Positive allosteric modulator
Details
TriazolamGABA(A) Receptor Benzodiazepine Binding Site (Protein Group)Protein groupHumans
Yes
Ligand
Details