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      Structure of a human synaptic GABA-A receptor

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          Abstract

          Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the GABA-A receptor. Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA-A receptor is also a prolific target for therapeutic, illicit, and recreational drugs, including benzodiazepines, barbiturates, anesthetics and ethanol. We present high resolution cryo-electron microscopy structures of the human α1β2γ2 GABA-A receptor, the predominant isoform in the adult brain. The receptor is bound to 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 receptors. 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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          Most cited references63

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          LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions.

          The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. The output is a colour, or black-and-white, PostScript file giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities. The program is completely general for any ligand and can also be used to show other types of interaction in proteins and nucleic acids. It was designed to facilitate the rapid inspection of many enzyme complexes, but has found many other applications.
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            Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins.

            Formation of well-ordered crystals of membrane proteins is a bottleneck for structure determination by X-ray crystallography. Nevertheless, one can increase the probability of successful crystallization by precrystallization screening, a process by which one analyzes the monodispersity and stability of the protein-detergent complex. Traditionally, this has required microgram to milligram quantities of purified protein and a concomitant investment of time and resources. Here, we describe a rapid and efficient precrystallization screening strategy in which the target protein is covalently fused to green fluorescent protein (GFP) and the resulting unpurified protein is analyzed by fluorescence-detection size-exclusion chromatography (FSEC). This strategy requires only nanogram quantities of unpurified protein and allows one to evaluate localization and expression level, the degree of monodispersity, and the approximate molecular mass. We show the application of this precrystallization screening to four membrane proteins derived from prokaryotic or eukaryotic organisms.
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              Structure, function, and modulation of GABA(A) receptors.

              The GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABA(A) receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABA(A) receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                22 May 2018
                27 June 2018
                July 2018
                27 December 2018
                : 559
                : 7712
                : 67-72
                Affiliations
                Departments of Neuroscience and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
                Author notes
                [# ]Correspondence and requests for materials should be addressed to ryan.hibbs@ 123456utsouthwestern.edu
                Article
                NIHMS969002
                10.1038/s41586-018-0255-3
                6220708
                29950725
                a98dcf08-0ae6-4ef0-b0d0-2fc24e3a9f12

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