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Shared structural m...
Shared structural mechanisms of general anaesthetics and benzodiazepines
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Kim, J. J. (author)
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Gharpure, A. (author)
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Teng, J. (author)
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- Zhuang, Yuxuan (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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- Howard, Rebecca J. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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Zhu, S. (author)
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Noviello, C. M. (author)
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Walsh, R.M., Jr. (author)
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- Lindahl, Erik, 1972- (author)
- Stockholms universitet,KTH,SeRC - Swedish e-Science Research Centre,Biofysik,Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),KTH Royal Institute of Technology, Sweden
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Hibbs, R. E. (author)
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(creator_code:org_t)
- 2020-09-02
- 2020
- English.
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In: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 585:7824, s. 303-308
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Abstract
Subject headings
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- Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1–5. 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 GABAA 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 GABAA 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 GABAA 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- 4 aminobutyric acid
- 4 aminobutyric acid A receptor
- benzodiazepine derivative
- bicuculline
- diazepam
- etomidate
- flumazenil
- intravenous anesthetic agent
- phenobarbital
- picrotoxin
- propofol
- 4 aminobutyric acid A receptor blocking agent
- anesthetic agent
- barbituric acid derivative
- ligand
- anesthetic
- biochemistry
- inhibition
- membrane
- physiological response
- protein
- signaling
- affinity labeling
- allosterism
- Article
- complex formation
- conformational transition
- controlled study
- cryoelectron microscopy
- drug binding site
- human
- human cell
- molecular dynamics
- mutagenesis
- priority journal
- binding competition
- binding site
- chemistry
- conformation
- drug effect
- electrophysiology
- metabolism
- molecular model
- ultrastructure
- Allosteric Regulation
- Anesthetics
- General
- Barbiturates
- Benzodiazepines
- Binding Sites
- Binding
- Competitive
- GABA-A Receptor Antagonists
- gamma-Aminobutyric Acid
- Humans
- Ligands
- Models
- Molecular
- Molecular Conformation
- Molecular Dynamics Simulation
- Receptors
- GABA-A
Publication and Content Type
- ref (subject category)
- art (subject category)
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Nature
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- By the author/editor
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Kim, J. J.
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Gharpure, A.
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Teng, J.
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Zhuang, Yuxuan
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Howard, Rebecca ...
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Zhu, S.
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show more...
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Noviello, C. M.
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Walsh, R.M., Jr.
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Lindahl, Erik, 1 ...
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Hibbs, R. E.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Physiology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Nature
- By the university
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Royal Institute of Technology
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Stockholm University