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- PDB-8bhm: GABA-A receptor a5 homomer - a5V3 - DMCM -

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Basic information

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


inner ear receptor cell development / GABA receptor activation / GABA receptor binding / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation / postsynaptic specialization membrane / gamma-aminobutyric acid signaling pathway ...inner ear receptor cell development / GABA receptor activation / GABA receptor binding / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation / postsynaptic specialization membrane / gamma-aminobutyric acid signaling pathway / synaptic transmission, GABAergic / neuronal cell body membrane / cochlea development / associative learning / transmembrane transporter complex / chloride channel complex / regulation of postsynaptic membrane potential / behavioral fear response / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / chloride transmembrane transport / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / GABA-ergic synapse / 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 transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / 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 transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / 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-R63 / Gamma-aminobutyric acid receptor subunit alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsMiller, P.S. / Malinauskas, T.M. / Hardwick, S.W. / Chirgadze, D.Y.
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 31, 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
Revision 1.4Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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)207,96715
Polymers205,2905
Non-polymers2,67810
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "B"
d_2ens_1chain "C"
d_3ens_1chain "A"
d_4ens_1chain "E"
d_5ens_1chain "D"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1ASNASND1 - 336
d_12ens_1NAGNAGE
d_13ens_1MCMMCMF
d_21ens_1ASNASNG1 - 336
d_22ens_1NAGNAGH
d_23ens_1MCMMCMI
d_31ens_1ASNASNA1 - 336
d_32ens_1NAGNAGB
d_33ens_1MCMMCMC
d_41ens_1ASNASNM1 - 336
d_42ens_1NAGNAGN
d_43ens_1MCMMCMO
d_51ens_1ASNASNJ1 - 336
d_52ens_1NAGNAGK
d_53ens_1MCMMCML

NCS oper:
IDCodeMatrixVector
1given(0.309645333687, -0.950852126396, -3.24579826561E-5), (0.950852126933, 0.309645333295, 1.66022417086E-5), (-5.73581397397E-6, -3.60035485183E-5, 0.999999999335)272.295398735, -43.2382777103, 0.00722142465256
2given(0.309093125735, 0.951031776345, 2.08498867371E-6), (-0.951031776114, 0.30909312561, 2.28675587824E-5), (2.11033193835E-5, -9.05109570354E-6, 0.999999999736)-43.1657412989, 272.397564773, 0.00458074258569
3given(-0.808550842131, 0.588426302081, -0.000150694983595), (-0.588426321371, -0.808550816801, 0.000202405058328), (-2.74409207948E-6, 0.000252327675209, 0.999999968162)202.430805886, 397.627779136, -0.0387831661344
4given(-0.80928148296, -0.587421037039, 8.11339784334E-5), (0.587421031476, -0.809281486788, -8.32041317949E-5), (0.00011453608408, -1.96757578683E-5, 0.999999993247)397.60380318, 202.72067567, -0.00884305070784

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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


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-R63 / methyl 4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-carboxylate


Mass: 314.336 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C17H18N2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY
Has protein modificationY

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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 subunit of homopentamer complex called 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
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2500 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 23.1 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refinedev_4674refinement
PHENIXdev_4674refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53252 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 134.25 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001114135
ELECTRON MICROSCOPYf_angle_d0.332919240
ELECTRON MICROSCOPYf_chiral_restr0.03712160
ELECTRON MICROSCOPYf_plane_restr0.00272525
ELECTRON MICROSCOPYf_dihedral_angle_d6.495130
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2DELECTRON MICROSCOPYNCS constraints4.55977976449E-13
ens_1d_3DELECTRON MICROSCOPYNCS constraints1.39957976975E-10
ens_1d_4DELECTRON MICROSCOPYNCS constraints8.9491467274E-12
ens_1d_5DELECTRON MICROSCOPYNCS constraints1.2483141254E-12

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