TY - JOUR
T1 - Structure of a human synaptic GABAA receptor
AU - Zhu, Shaotong
AU - Noviello, Colleen M.
AU - Teng, Jinfeng
AU - Walsh, Richard M.
AU - Kim, Jeong Joo
AU - Hibbs, Ryan E
N1 - Funding Information:
We thank D. Cawley for antibody production, X. Bai for electron microscopy discussion, P. Emsley for guidance on glycosylation tools in Coot, W. Costello for initial construct screening and all members of the Hibbs laboratory for discussion. Single-particle cryo-EM data were collected at the University of Texas Southwestern Medical Center Cryo-Electron Microscopy Facility, which is supported by the CPRIT Core Facility Support Award RP170644. We thank D. Nicastro and D. Stoddard for support in facility access and data acquisition. R.W. acknowledges support from the Sara and Frank McKnight Fund for Biochemical Research and the NIH (T32GM008203). R.E.H. is supported by a McKnight Scholar Award, The Welch Foundation (I-1812) and the NIH (DA037492, DA042072, and NS095899).
Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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 (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 α1β2γ2 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.
AB - 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 (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 α1β2γ2 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.
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U2 - 10.1038/s41586-018-0255-3
DO - 10.1038/s41586-018-0255-3
M3 - Article
C2 - 29950725
AN - SCOPUS:85049604256
SN - 0028-0836
VL - 559
SP - 67
EP - 88
JO - Nature
JF - Nature
IS - 7712
ER -