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Yorodumi- PDB-8vrn: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with ... -
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-Basic information
Entry | Database: PDB / ID: 8vrn | ||||||
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Title | Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus PPTQ | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / complex / PPTQ / drug modulation / GABAA receptor | ||||||
Function / homology | Function and homology information benzodiazepine receptor activity / GABA receptor complex / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation ...benzodiazepine receptor activity / GABA receptor complex / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / 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 / chloride channel activity / adult behavior / cochlea development / Signaling by ERBB4 / chloride channel complex / regulation of postsynaptic membrane potential / transmembrane transporter complex / GABA-ergic synapse / 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 / postsynaptic membrane / postsynapse / dendritic spine / 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: 2.57 Å | ||||||
Authors | Chojnacka, W. / Teng, J. / Kim, J.J. / Jensen, A.A. / Hibbs, R.E. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2024 Title: Structural insights into GABA receptor potentiation by Quaalude. Authors: Weronika Chojnacka / Jinfeng Teng / Jeong Joo Kim / Anders A Jensen / Ryan E Hibbs / Abstract: Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in ...Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA receptor modulation through transmembrane binding sites. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8vrn.cif.gz | 423.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8vrn.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8vrn.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8vrn_validation.pdf.gz | 2 MB | Display | wwPDB validaton report |
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Full document | 8vrn_full_validation.pdf.gz | 2 MB | Display | |
Data in XML | 8vrn_validation.xml.gz | 74.7 KB | Display | |
Data in CIF | 8vrn_validation.cif.gz | 109.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/vr/8vrn ftp://data.pdbj.org/pub/pdb/validation_reports/vr/8vrn | HTTPS FTP |
-Related structure data
Related structure data | 43485MC 8vqyC 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 / Cell line (production host): HEK293S GnTI- / 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 / Cell line (production host): HEK293S GnTI- / 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 / Cell line (production host): HEK293S GnTI- / 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) / Gene: LC / Cell line (production host): Sf9 / Production host: Spodoptera (butterflies/moths) #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) / Gene: Ighg / Cell line (production host): Sf9 / Production host: Spodoptera (butterflies/moths) |
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-Sugars , 3 types, 7 molecules
#6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: Polysaccharide | Source method: isolated from a genetically manipulated source #8: 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 |
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-Non-polymers , 5 types, 12 molecules
#9: Chemical | #10: Chemical | Mass: 312.365 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H16N2O / Feature type: SUBJECT OF INVESTIGATION #11: Chemical | ChemComp-PTY / #12: Chemical | ChemComp-POV / ( | #13: 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 PPTQ Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Value: 0.368767 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K |
-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: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 227450 / Symmetry type: POINT | ||||||||||||||||||||||||
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