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- EMDB-22035: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with ... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-22035 | ||||||||||||||||||
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Title | Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus phenobarbital | ||||||||||||||||||
![]() | Human GABAA receptor alpha1-beta2-gamma2 subtype | ||||||||||||||||||
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![]() | Ion channel / Cys-loop receptor / pentametic ligand gated channel / GABAA receptor / MEMBRANE PROTEIN | ||||||||||||||||||
Function / homology | ![]() benzodiazepine receptor activity / GABA receptor complex / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation ...benzodiazepine receptor activity / GABA receptor complex / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / neurotransmitter receptor activity / adult behavior / cochlea development / chloride channel activity / Signaling by ERBB4 / chloride channel complex / transmembrane transporter complex / GABA-ergic synapse / regulation of postsynaptic membrane potential / chloride transmembrane transport / dendrite membrane / post-embryonic development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cytoplasmic vesicle membrane / chemical synaptic transmission / postsynapse / neuron projection / axon / synapse / extracellular exosome / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() ![]() | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||||||||
![]() | Kim JJ / Gharpure A | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Shared structural mechanisms of general anaesthetics and benzodiazepines. 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 / ![]() ![]() 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. | ||||||||||||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 9.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 25.8 KB 25.8 KB | Display Display | ![]() |
Images | ![]() | 114.7 KB | ||
Filedesc metadata | ![]() | 7.9 KB | ||
Others | ![]() ![]() | 65.3 MB 65.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6x3wMC ![]() 6x3sC ![]() 6x3tC ![]() 6x3uC ![]() 6x3vC ![]() 6x3xC ![]() 6x3zC ![]() 6x40C M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Human GABAA receptor alpha1-beta2-gamma2 subtype | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.825 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: Human GABAA receptor alpha1-beta2-gamma2 subtype
File | emd_22035_half_map_1.map | ||||||||||||
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Annotation | Human GABAA receptor alpha1-beta2-gamma2 subtype | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Human GABAA receptor alpha1-beta2-gamma2 subtype
File | emd_22035_half_map_2.map | ||||||||||||
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Annotation | Human GABAA receptor alpha1-beta2-gamma2 subtype | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
+Entire : Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with...
+Supramolecule #1: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with...
+Supramolecule #2: Human GABA-A receptor alpha1-beta2-gamma2 subtype
+Supramolecule #3: IgG2b/kappa antibody
+Macromolecule #1: Gamma-aminobutyric acid receptor subunit beta-2
+Macromolecule #2: Gamma-aminobutyric acid receptor subunit alpha-1
+Macromolecule #3: Gamma-aminobutyric acid receptor subunit gamma-2
+Macromolecule #4: Kappa Fab Light Chain
+Macromolecule #5: IgG2b Fab Heavy Chain
+Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #10: GAMMA-AMINO-BUTANOIC ACID
+Macromolecule #11: 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 8 mg/mL | |||||||||
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Buffer | pH: 7.4 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 80 sec. / Pretreatment - Atmosphere: AIR | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 3.5 second blot. |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 6682 / Average electron dose: 69.59 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | ![]() PDB-6x3w: |