EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Cryo-EM structures reveal native GABA receptor assemblies and pharmacology.
ジャーナル・号・ページ	Nature, Vol. 622, Issue 7981, Page 195-201, Year 2023
掲載日	2023年9月20日
著者	Chang Sun / Hongtao Zhu / Sarah Clark / Eric Gouaux /
PubMed 要旨	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.
リンク	Nature / PubMed:37730991 / PubMed Central
手法	EM (単粒子)
解像度	2.5 - 3.06 Å
構造データ	29350 8foi EMDB-29350, PDB-8foi: Native GABA-A receptor from the mouse brain, alpha1-beta2-gamma2 subtype, in complex with GABA and allopregnanolone 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 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 手法: EM (単粒子) / 解像度: 2.89 Å
化合物	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 / 1-O-(1-O,2-O-ジオクタノイル-L-グリセロ-3-ホスホ)-D-myo-イノシト-ル4,5-ビスりん酸 ChemComp-D12: DODECANE / ドデカン ChemComp-OCT: N-OCTANE / オクタン ChemComp-POV: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / リン脂質YM ChemComp-ABU: GAMMA-AMINO-BUTANOIC ACID / GABA ChemComp-Y4B: allopregnanolone / アロプレグナノロン ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-R5R: Zolpidem / ゾルピデム / 薬剤YM ChemComp-YNL: (5M)-1-(2-aminoethyl)-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one / 7-クロロ-5-(2-フルオロフェニル)-1,3-ジヒドロ-1-(2-アミノエチル)-2H-1,4-ベンゾジアゼピン-(以下略)
由来	mus musculus (ハツカネズミ)
キーワード	MEMBRANE PROTEIN / ligand-gated ion channel / cys-loop receptor / neurotransmitter receptor