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Yorodumi- PDB-8dd3: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8dd3 | |||||||||||||||||||||
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Title | Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus DMCM | |||||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN/IMMUNE SYSTEM / Human GABAA receptor / DMCM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | |||||||||||||||||||||
Function / homology | Function and homology information GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / inhibitory synapse assembly ...GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / benzodiazepine receptor activity / cellular response to histamine / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / postsynaptic specialization membrane / gamma-aminobutyric acid signaling pathway / neurotransmitter receptor activity / adult behavior / cochlea development / chloride channel activity / Signaling by ERBB4 / chloride channel complex / GABA-ergic synapse / transmembrane transporter complex / 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 / postsynapse / chemical synaptic transmission / postsynaptic membrane / neuron projection / axon / synapse / extracellular exosome / plasma membrane Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | |||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||||||||||||||
Authors | Zhu, S. / Hibbs, R.E. | |||||||||||||||||||||
Funding support | United States, 6items
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Citation | Journal: Nat Commun / Year: 2022 Title: Structural and dynamic mechanisms of GABA receptor modulators with opposing activities. Authors: Shaotong Zhu / Akshay Sridhar / Jinfeng Teng / Rebecca J Howard / Erik Lindahl / Ryan E Hibbs / Abstract: γ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and ...γ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA receptor allosteric modulators acting through a common site can have diverging activities. | |||||||||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8dd3.cif.gz | 407.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8dd3.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8dd3.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8dd3_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8dd3_full_validation.pdf.gz | 1.7 MB | Display | |
Data in XML | 8dd3_validation.xml.gz | 66.3 KB | Display | |
Data in CIF | 8dd3_validation.cif.gz | 97.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dd/8dd3 ftp://data.pdbj.org/pub/pdb/validation_reports/dd/8dd3 | HTTPS FTP |
-Related structure data
Related structure data | 27333MC 8dd2C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Gamma-aminobutyric acid receptor subunit ... , 3 types, 5 molecules ACBDE
#1: Protein | Mass: 41810.086 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GABRB2 / Production host: Homo sapiens (human) / References: UniProt: P47870 #2: Protein | Mass: 41061.211 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GABRA1 / Production host: Homo sapiens (human) / References: UniProt: P14867 #3: Protein | | Mass: 47673.109 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GABRG2 / Production host: Homo sapiens (human) / References: UniProt: P18507 |
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-Antibody , 2 types, 4 molecules ILJK
#4: Antibody | Mass: 23505.943 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) #5: Antibody | Mass: 49811.043 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) |
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-Sugars , 4 types, 7 molecules
#6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: Polysaccharide | alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #8: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #9: Sugar | |
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-Non-polymers , 2 types, 5 molecules
#10: Chemical | #11: Chemical | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus DMCM Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES | |||||||||||||||
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Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||
Source (recombinant) | Organism: Homo sapiens (human) | |||||||||||||||
Buffer solution | pH: 7.4 | |||||||||||||||
Buffer component |
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Specimen | Conc.: 6.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3 | |||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: 3.5 second blot |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 11149 |
EM imaging optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||||||||
3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1166570 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT |