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	Shared structural mechanisms of general anaesthetics and benzodiazepines.
Journal, issue, pages	Nature, Vol. 585, Issue 7824, Page 303-308, Year 2020
Publish date	Sep 2, 2020
Authors	Jeong Joo Kim / Anant Gharpure / Jinfeng Teng / Yuxuan Zhuang / Rebecca J Howard / Shaotong Zhu / Colleen M Noviello / Richard M Walsh / Erik Lindahl / Ryan E Hibbs /
PubMed Abstract	Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity in the brain. However, direct ...Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity in the brain. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
External links	Nature / PubMed:32879488 / PubMed Central
Methods	EM (single particle)
Resolution	2.55 - 3.5 Å
Structure data	22031 6x3s EMDB-22031, PDB-6x3s: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with bicuculline methbromide Method: EM (single particle) / Resolution: 3.12 Å 22032 6x3t EMDB-22032, PDB-6x3t: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus propofol Method: EM (single particle) / Resolution: 2.55 Å 22033 6x3u EMDB-22033, PDB-6x3u: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus flumazenil Method: EM (single particle) / Resolution: 3.5 Å 22034 6x3v EMDB-22034, PDB-6x3v: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus etomidate Method: EM (single particle) / Resolution: 3.5 Å 22035 6x3w EMDB-22035, PDB-6x3w: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus phenobarbital Method: EM (single particle) / Resolution: 3.3 Å 22036 6x3x EMDB-22036, PDB-6x3x: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus diazepam Method: EM (single particle) / Resolution: 2.92 Å 22037 6x3z EMDB-22037, PDB-6x3z: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA Method: EM (single particle) / Resolution: 3.23 Å 22038 6x40 EMDB-22038, PDB-6x40: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus picrotoxin Method: EM (single particle) / Resolution: 2.86 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-J94: (5S)-6,6-dimethyl-5-[(6R)-8-oxo-6,8-dihydrofuro[3,4-e][1,3]benzodioxol-6-yl]-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-6-ium ChemComp-MAN: alpha-D-mannopyranose / Mannose ChemComp-ABU: GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitorYM / Γ-Aminobutyric acid ChemComp-PFL: 2,6-BIS(1-METHYLETHYL)PHENOL / Propofol ChemComp-FYP: ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / antagonistYM / Flumazenil ChemComp-V8D: Etomidate / Etomidate ChemComp-UQA: 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione / medicationYM / Phenobarbital ChemComp-DZP: 7-CHLORO-1-METHYL-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE / Diazepam 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 / Picrotoxin
Source	homo sapiens (human) mus musculus (house mouse)
Keywords	MEMBRANE PROTEIN / Ion channel / Cys-loop receptor / pentametic ligand gated channel / GABAA receptor / TRANSPORT PROTEIN / pentametic ligand gated ion channel