+
検索条件

キーワード
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

-
Structure paper

タイトル	GABA receptor signalling mechanisms revealed by structural pharmacology.
ジャーナル・号・ページ	Nature, Vol. 565, Issue 7740, Page 454-459, Year 2019
掲載日	2019年1月2日
著者	Simonas Masiulis / Rooma Desai / Tomasz Uchański / Itziar Serna Martin / Duncan Laverty / Dimple Karia / Tomas Malinauskas / Jasenko Zivanov / Els Pardon / Abhay Kotecha / Jan Steyaert / Keith W Miller / A Radu Aricescu /
PubMed 要旨	Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the ...Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators.
リンク	Nature / PubMed:30602790 / PubMed Central
手法	EM (単粒子)
解像度	3.04 - 3.69 Å
構造データ	0275 6hug EMDB-0275, PDB-6hug: CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with picrotoxin and megabody Mb38. 手法: EM (単粒子) / 解像度: 3.1 Å 0279 6huj EMDB-0279, PDB-6huj: CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with picrotoxin, GABA and megabody Mb38. 手法: EM (単粒子) / 解像度: 3.04 Å 0280 6huk EMDB-0280, PDB-6huk: CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with bicuculline and megabody Mb38. 手法: EM (単粒子) / 解像度: 3.69 Å 0282 6huo EMDB-0282, PDB-6huo: CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with alprazolam (Xanax), GABA and megabody Mb38. 手法: EM (単粒子) / 解像度: 3.26 Å 0283 6hup EMDB-0283, PDB-6hup: CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with diazepam (Valium), GABA and megabody Mb38. 手法: EM (単粒子) / 解像度: 3.58 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-RI5: (1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-2-yl)hexahydro-3,6-methano-1,5,7-trioxacyclopenta[ij]c / toxinYM ChemComp-ABU: GAMMA-AMINO-BUTANOIC ACID / GABA ChemComp-H0Z: bicuculline methochloride / ビククリン / アンタゴニスト, alkaloidYM ChemComp-08H: 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine / アルプラゾラム ChemComp-DZP: 7-CHLORO-1-METHYL-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE / ジアゼパム
由来	homo sapiens (ヒト) lama glama (ラマ) bos taurus (ウシ)
キーワード	MEMBRANE PROTEIN / GABAAR / PTX / Membrane / Channel / Nanobody / Megabody / Cys-loop / PLGIC / Inhibition / Signalling / CNS / Neurons / Chloride / Ion / GABA / Picrotoxin / BCC / Bicuculline / Antagonist / Cys-loop receptor