6HUO

CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with alprazolam (Xanax), GABA and megabody Mb38.

6HUO の概要

• エントリーDOI: 10.2210/pdb6huo/pdb
• EMDBエントリー: 0282
• 分子名称: Gamma-aminobutyric acid receptor subunit alpha-1,Gamma-aminobutyric acid receptor subunit alpha-1, [(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, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, ... (11 entities in total)
• 機能のキーワード: gabaar, membrane protein, plgic, cys-loop receptor
• 由来する生物種: Bos taurus (Bovine); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 337001.91

構造登録者

Masiulis, S.,Desai, R.,Uchanski, T.,Serna Martin, I.,Laverty, D.,Karia, D.,Malinauskas, T.,Jasenko, Z.,Pardon, E.,Kotecha, A.,Steyaert, J.,Miller, K.W.,Aricescu, A.R. (登録日: 2018-10-09, 公開日: 2019-01-02, 最終更新日: 2024-11-06)

主引用文献

Masiulis, S.,Desai, R.,Uchanski, T.,Serna Martin, I.,Laverty, D.,Karia, D.,Malinauskas, T.,Zivanov, J.,Pardon, E.,Kotecha, A.,Steyaert, J.,Miller, K.W.,Aricescu, A.R.
GABAAreceptor signalling mechanisms revealed by structural pharmacology.
Nature, 565:454-459, 2019

PubMed Abstract: 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.

PubMed: 30602790
DOI: 10.1038/s41586-018-0832-5

実験手法

ELECTRON MICROSCOPY (3.26 Å)