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- EMDB-16055: GABA-A receptor a5 homomer - a5V3 - RO5211223 -

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Basic information

Entry
Database: EMDB / ID: EMD-16055
TitleGABA-A receptor a5 homomer - a5V3 - RO5211223
Map data
Sample
  • Complex: GABA-A receptor a5 homomer - a5V3 - RO5211223
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-5
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone
KeywordspLGIC GABA Neurotransmission / MEMBRANE PROTEIN
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 / gamma-aminobutyric acid signaling pathway ...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 / gamma-aminobutyric acid signaling pathway / synaptic transmission, GABAergic / neuronal cell body membrane / cochlea development / chloride channel complex / associative learning / 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
Gamma-aminobutyric acid receptor subunit alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.67 Å
AuthorsMiller PS / Malinauskas TM / Hardwick SW / Chirgadze DY
Funding support United Kingdom, 1 items
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, 2022-
Header (metadata) releaseNov 1, 2023-
Map releaseNov 1, 2023-
UpdateDec 27, 2023-
Current statusDec 27, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16055.png

Downloads & links

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Map

FileDownload / File: emd_16055.map.gz / Format: CCP4 / Size: 536.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 520 pix.
= 339.04 Å		0.65 Å/pix.
x 520 pix.
= 339.04 Å		0.65 Å/pix.
x 520 pix.
= 339.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.652 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.121
Minimum - Maximum-0.15394513 - 0.38803998
Average (Standard dev.)0.00029207708 (±0.009913047)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions520520520
Spacing520520520
CellA=B=C: 339.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_16055_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_16055_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : GABA-A receptor a5 homomer - a5V3 - RO5211223

EntireName: GABA-A receptor a5 homomer - a5V3 - RO5211223
Components
  • Complex: GABA-A receptor a5 homomer - a5V3 - RO5211223
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-5
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone

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Supramolecule #1: GABA-A receptor a5 homomer - a5V3 - RO5211223

SupramoleculeName: GABA-A receptor a5 homomer - a5V3 - RO5211223 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 205 KDa

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Macromolecule #1: Gamma-aminobutyric acid receptor subunit alpha-5

MacromoleculeName: Gamma-aminobutyric acid receptor subunit alpha-5 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.05791 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QMPTSSVKDE TNDNITIFTR ILDGLLDGYD NRLRPGLGER ITQVRTDMYV NSFGPVSDTE MEYTIDIFFA QTWKDERLRF KGPMQRLPL NNLLASKIWT PDTFFHNGKK SFAHWMTTPN RMLRIWNDGR VLYTLRLTIS AECPMDLEDF PMDEQNCPLK F GSYAYPNS ...String:
QMPTSSVKDE TNDNITIFTR ILDGLLDGYD NRLRPGLGER ITQVRTDMYV NSFGPVSDTE MEYTIDIFFA QTWKDERLRF KGPMQRLPL NNLLASKIWT PDTFFHNGKK SFAHWMTTPN RMLRIWNDGR VLYTLRLTIS AECPMDLEDF PMDEQNCPLK F GSYAYPNS EVVYVWTNGS TKSVVVAEDG SRLNQYHLMG QTVGTENIST STGEYTIMTA HFHLKRKIGY FVIQTYLPCI MT VILSQVS FWLNRESVAA RTVFGVTTVL TMTTLSISAR NSLPKVAYAT AMDWFIAVCY AFVFSALLEF AFVNYITKSQ PAR AAKIDK MSRIVFPILF GTFNLVYWAT YLNGTTETSQ VAPA

UniProtKB: Gamma-aminobutyric acid receptor subunit alpha-5, Gamma-aminobutyric acid receptor subunit alpha-5

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #3: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-me...

MacromoleculeName: [1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone
type: ligand / ID: 3 / Number of copies: 5 / Formula: QKF
Molecular weightTheoretical: 442.488 Da
Chemical component information

ChemComp-QKF:
[1,1-bis(oxidanylidene)-1,4-thiazinan-4-yl]-[6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.45 sec. / Average electron dose: 49.27 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 15289
FSC plot (resolution estimation)

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