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- PDB-8bhb: GABA-A receptor a5 homomer - a5V3 - RO154513 -

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Basic information

Entry
Database: PDB / ID: 8bhb
TitleGABA-A receptor a5 homomer - a5V3 - RO154513
ComponentsGamma-aminobutyric acid receptor subunit alpha-5
KeywordsMEMBRANE PROTEIN / pLGIC GABA Neurotransmission
Function / homology
Function and homology information


inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / innervation / postsynaptic specialization membrane / synaptic transmission, GABAergic ...inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / GABA-A receptor activity / GABA-A receptor complex / GABA receptor binding / innervation / postsynaptic specialization membrane / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / neuronal cell body membrane / cochlea development / associative learning / chloride channel complex / GABA-ergic synapse / regulation of postsynaptic membrane potential / behavioral fear response / chloride transmembrane transport / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / signaling receptor activity / presynaptic membrane / postsynapse / neuron projection / synapse / signal transduction / nucleoplasm / plasma membrane / cytosol
Similarity search - Function
Gamma-aminobutyric-acid A receptor, alpha 5 subunit / : / Gamma-aminobutyric-acid A receptor, alpha subunit / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor ...Gamma-aminobutyric-acid A receptor, alpha 5 subunit / : / Gamma-aminobutyric-acid A receptor, alpha subunit / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
Chem-EIE / Gamma-aminobutyric acid receptor subunit alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.54 Å
AuthorsMiller, P.S. / Malinauskas, T.M. / Hardwick, S.W. / Chirgadze, D.Y. / Wahid, A.A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: The molecular basis of drug selectivity for α5 subunit-containing GABA receptors.
Authors: Vikram Babu Kasaragod / Tomas Malinauskas / Ayla A Wahid / Judith Lengyel / Frederic Knoflach / Steven W Hardwick / Charlotte F Jones / Wan-Na Chen / Xavier Lucas / Kamel El Omari / Dimitri ...Authors: Vikram Babu Kasaragod / Tomas Malinauskas / Ayla A Wahid / Judith Lengyel / Frederic Knoflach / Steven W Hardwick / Charlotte F Jones / Wan-Na Chen / Xavier Lucas / Kamel El Omari / Dimitri Y Chirgadze / A Radu Aricescu / Giuseppe Cecere / Maria-Clemencia Hernandez / Paul S Miller /
Abstract: α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to ...α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.
History
DepositionOct 30, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 15, 2023Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gamma-aminobutyric acid receptor subunit alpha-5
B: Gamma-aminobutyric acid receptor subunit alpha-5
C: Gamma-aminobutyric acid receptor subunit alpha-5
D: Gamma-aminobutyric acid receptor subunit alpha-5
E: Gamma-aminobutyric acid receptor subunit alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,02715
Polymers205,2905
Non-polymers2,73810
Water1,17165
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27870 Å2
ΔGint-144 kcal/mol
Surface area65050 Å2

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Components

#1: Protein
Gamma-aminobutyric acid receptor subunit alpha-5 / GABA(A) receptor subunit alpha-5


Mass: 41057.910 Da / Num. of mol.: 5
Mutation: I79M,T82N,V98I,R101A,S103T,I142F,N145W,K151R,L152M,L155I,E156W,D157N,T160R,L161V,M165L,Q176D,A184E,H185Q,A186N,P287A,I336L,T340F,F344I,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRA5 / Production host: Homo sapiens (human) / References: UniProt: P31644
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical
ChemComp-EIE / ethyl 8-[(azanylidene-$l^{4}-azanylidene)amino]-5-methyl-6-oxidanylidene-4~{H}-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate / Ro15-4513


Mass: 326.310 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C15H14N6O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GABA-A a5 homopentamer a5V3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.205 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingAverage exposure time: 1.5 sec. / Electron dose: 46.9 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18185 / Symmetry type: POINT

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