- EMDB-0283: CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R... -
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基本情報
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データベース: EMDB / ID: EMD-0283
タイトル
CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with diazepam (Valium), GABA and megabody Mb38.
マップデータ
Synaptic human full-length a1b3g2L GABAAR in complex with diazepam, GABA and megabody Mb38. Sharpened and filtered map (generated with Relion post-processing).
試料
複合体: Human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with diazepam (Valium), GABA and megabody Mb38.
Biotechnology and Biological Sciences Research Council
BB/M024709/1
英国
Cancer Research UK
C20724/A14414
英国
Human Frontier Science Program
RGP0065/2014
英国
Swiss National Science Foundation
168735
スイス
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM 58448
米国
引用
ジャーナル: Nature / 年: 2019 タイトル: GABA receptor signalling mechanisms revealed by structural pharmacology. 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 / ...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 / 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.
ダウンロード / ファイル: emd_0283.map.gz / 形式: CCP4 / 大きさ: 103 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈
Synaptic human full-length a1b3g2L GABAAR in complex with diazepam, GABA and megabody Mb38. Sharpened and filtered map (generated with Relion post-processing).