Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM structures reveal native GABA receptor assemblies and pharmacology.
Journal, issue, pages	Nature, Vol. 622, Issue 7981, Page 195-201, Year 2023
Publish date	Sep 20, 2023
Authors	Chang Sun / Hongtao Zhu / Sarah Clark / Eric Gouaux /
PubMed Abstract	Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and ...Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
External links	Nature / PubMed:37730991 / PubMed Central
Methods	EM (single particle)
Resolution	2.5 - 3.06 Å
Structure data	29350 8foi EMDB-29350, PDB-8foi: Native GABA-A receptor from the mouse brain, alpha1-beta2-gamma2 subtype, in complex with GABA and allopregnanolone Method: EM (single particle) / Resolution: 2.5 Å 29727 8g4n EMDB-29727, PDB-8g4n: Native GABA-A receptor from the mouse brain, alpha1-beta2-gamma2 subtype, in complex with GABA, Zolpidem, and endogenous neurosteroids Method: EM (single particle) / Resolution: 2.67 Å 29728 8g4o EMDB-29728, PDB-8g4o: Native GABA-A receptor from the mouse brain, alpha1-beta2-gamma2 subtype, in complex with didesethylflurazepam and endogenous GABA Method: EM (single particle) / Resolution: 3.06 Å 29733 8g4x EMDB-29733, PDB-8g4x: Native GABA-A receptor from the mouse brain, meta-alpha1-alpha3-beta2-gamma2 subtype, in complex with GABA and allopregnanolone Method: EM (single particle) / Resolution: 2.56 Å 29741 8g5f EMDB-29741, PDB-8g5f: Native GABA-A receptor from the mouse brain, ortho-alpha1-alpha3-beta2-gamma2 subtype, in complex with GABA and allopregnanolone Method: EM (single particle) / Resolution: 2.64 Å 29742 8g5g EMDB-29742, PDB-8g5g: Native GABA-A receptor from the mouse brain, meta-alpha1-alpha3-beta2-gamma2 subtype, in complex with GABA, Zolpidem, and endogenous neurosteroid Method: EM (single particle) / Resolution: 2.94 Å 29743 8g5h EMDB-29743, PDB-8g5h: Native GABA-A receptor from the mouse brain, ortho-alpha1-alpha3-beta2-gamma2 subtype, in complex with GABA, Zolpidem, and endogenous neurosteroid Method: EM (single particle) / Resolution: 2.89 Å
Chemicals	ChemComp-PIO: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate ChemComp-D12: DODECANE / Dodecane ChemComp-OCT: N-OCTANE / Octane ChemComp-POV: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipidYM / POPC ChemComp-ABU: GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitorYM / Γ-Aminobutyric acid ChemComp-Y4B: allopregnanolone ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-R5R: Zolpidem / medicationYM / Zolpidem ChemComp-YNL*: (5M)-1-(2-aminoethyl)-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
Source	mus musculus (house mouse)
Keywords	MEMBRANE PROTEIN / ligand-gated ion channel / cys-loop receptor / neurotransmitter receptor