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Volume 559 Issue 7712, 5 July 2018

Valium’s target

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the type A GABA receptor (GABAA). These receptors have a major role in psychological activity in the central nervous system — their dysfunction can lead to disorders such as epilepsy, anxiety and insomnia. They are also the target for drugs, including barbiturates, anaesthetics, alcohol, and the benzodiazepines diazepam (Valium) and alprazolam (Xanax). In this week’s issue, Ryan Hibbs and his colleagues report the structure of the predominant isoform of the receptor in the brain. Using cryo-electron microscopy the researchers reveal the human α1β2γ2 GABAA receptor bound to flumazenil, an overdose antidote, and GABA. Each subunit in this heteromeric receptor is a different colour, with the drugs bound shown as teal spheres. The team shows how the receptor is affected by benzodiazepines and reveal sites at specific interfaces between the protein subunits of the receptor that are potential targets for drug development.

Cover image: Shaotong Zhu, Hibbs Lab.

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