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Structure paper

TitleShared structural mechanisms of general anaesthetics and benzodiazepines.
Journal, issue, pagesNature, Vol. 585, Issue 7824, Page 303-308, Year 2020
Publish dateSep 2, 2020
AuthorsJeong 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 AbstractMost 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 linksNature / PubMed:32879488 / PubMed Central
MethodsEM (single particle)
Resolution2.55 - 3.5 Å
Structure data

EMDB-22031, PDB-6x3s:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with bicuculline methbromide
Method: EM (single particle) / Resolution: 3.12 Å

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

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

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

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

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

EMDB-22037, PDB-6x3z:
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA
Method: EM (single particle) / Resolution: 3.23 Å

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

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

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

ChemComp-PFL:
2,6-BIS(1-METHYLETHYL)PHENOL

ChemComp-FYP:
ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / antagonist*YM

ChemComp-V8D:
Etomidate

ChemComp-UQA:
5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione / medication*YM

ChemComp-DZP:
7-CHLORO-1-METHYL-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE

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 / toxin*YM

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ion channel / Cys-loop receptor / pentametic ligand gated channel / GABAA receptor / TRANSPORT PROTEIN / pentametic ligand gated ion channel

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