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- EMDB-40503: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-40503
TitleHuman GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus allopregnanolone
Map data
Sample
  • Complex: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and allopregnanolone
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-1
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit gamma-2
    • Protein or peptide: Kappa Fab Light Chain
    • Protein or peptide: IgG2b Fab Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: allopregnanolone
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
KeywordsIon channel / neurosteroids / TRANSPORT PROTEIN
Function / homology
Function and homology information


benzodiazepine receptor activity / GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / cellular response to histamine / inhibitory synapse assembly / GABA-A receptor activity / GABA-A receptor complex ...benzodiazepine receptor activity / GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / inner ear receptor cell development / GABA-gated chloride ion channel activity / cellular response to histamine / inhibitory synapse assembly / GABA-A receptor activity / GABA-A receptor complex / innervation / postsynaptic specialization membrane / neurotransmitter receptor activity / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / chloride channel activity / adult behavior / cochlea development / Signaling by ERBB4 / chloride channel complex / GABA-ergic synapse / 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 / chemical synaptic transmission / postsynapse / postsynaptic membrane / neuron projection / axon / synapse / extracellular exosome / plasma membrane
Similarity search - Function
Gamma-aminobutyric-acid A receptor, gamma 2 subunit / Gamma-aminobutyric acid receptor subunit gamma-1/4 / : / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / Gamma-aminobutyric-acid A receptor, beta 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. ...Gamma-aminobutyric-acid A receptor, gamma 2 subunit / Gamma-aminobutyric acid receptor subunit gamma-1/4 / : / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / Gamma-aminobutyric-acid A receptor, beta 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-1 / Gamma-aminobutyric acid receptor subunit gamma-2 / Gamma-aminobutyric acid receptor subunit beta-2
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsLegesse DH / Hibbs RE
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)DA047325 United States
Welch FoundationI-1812 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural insights into opposing actions of neurosteroids on GABA receptors.
Authors: Dagimhiwat H Legesse / Chen Fan / Jinfeng Teng / Yuxuan Zhuang / Rebecca J Howard / Colleen M Noviello / Erik Lindahl / Ryan E Hibbs /
Abstract: γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor ...γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
History
DepositionApr 14, 2023-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateNov 15, 2023-
Current statusNov 15, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40503.png

Downloads & links

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Map

FileDownload / File: emd_40503.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.0143
Minimum - Maximum-0.034266006 - 0.08797565
Average (Standard dev.)0.00025989878 (±0.0023423836)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 308.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40503_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40503_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with...

EntireName: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and allopregnanolone
Components
  • Complex: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and allopregnanolone
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-1
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit gamma-2
    • Protein or peptide: Kappa Fab Light Chain
    • Protein or peptide: IgG2b Fab Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: allopregnanolone
  • Ligand: GAMMA-AMINO-BUTANOIC ACID

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Supramolecule #1: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with...

SupramoleculeName: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and allopregnanolone
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 / Details: Human GABA-A receptor alpha1-beta2-gamma2 subtype
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gamma-aminobutyric acid receptor subunit beta-2

MacromoleculeName: Gamma-aminobutyric acid receptor subunit beta-2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.810086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVNDPSNMS LVKETVDRLL KGYDIRLRPD FGGPPVAVGM NIDIASIDMV SEVNMDYTLT MYFQQAWRDK RLSYNVIPLN LTLDNRVAD QLWVPDTYFL NDKKSFVHGV TVKNRMIRLH PDGTVLYGLR ITTTAACMMD LRRYPLDEQN CTLEIESYGY T TDDIEFYW ...String:
QSVNDPSNMS LVKETVDRLL KGYDIRLRPD FGGPPVAVGM NIDIASIDMV SEVNMDYTLT MYFQQAWRDK RLSYNVIPLN LTLDNRVAD QLWVPDTYFL NDKKSFVHGV TVKNRMIRLH PDGTVLYGLR ITTTAACMMD LRRYPLDEQN CTLEIESYGY T TDDIEFYW RGDDNAVTGV TKIELPQFSI VDYKLITKKV VFSTGSYPRL SLSFKLKRNI GYFILQTYMP SILITILSWV SF WINYDAS AARVALGITT VLTMTTINTH LRETLPKIPY VKAIDMYLMG CFVFVFMALL EYALVNYIFF SQPARAAAID RWS RIFFPV VFSFFNIVYW LYYVNVDGSG ATNFSLLKQA GDVEENPG

UniProtKB: Gamma-aminobutyric acid receptor subunit beta-2, Gamma-aminobutyric acid receptor subunit beta-2

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Macromolecule #2: Gamma-aminobutyric acid receptor subunit alpha-1

MacromoleculeName: Gamma-aminobutyric acid receptor subunit alpha-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.061211 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QPSLQDELKD NTTVFTRILD RLLDGYDNRL RPGLGERVTE VKTDIFVTSF GPVSDHDMEY TIDVFFRQSW KDERLKFKGP MTVLRLNNL MASKIWTPDT FFHNGKKSVA HNMTMPNKLL RITEDGTLLY TMRLTVRAEC PMHLEDFPMD AHACPLKFGS Y AYTRAEVV ...String:
QPSLQDELKD NTTVFTRILD RLLDGYDNRL RPGLGERVTE VKTDIFVTSF GPVSDHDMEY TIDVFFRQSW KDERLKFKGP MTVLRLNNL MASKIWTPDT FFHNGKKSVA HNMTMPNKLL RITEDGTLLY TMRLTVRAEC PMHLEDFPMD AHACPLKFGS Y AYTRAEVV YEWTREPARS VVVAEDGSRL NQYDLLGQTV DSGIVQSSTG EYVVMTTHFH LKRKIGYFVI QTYLPCIMTV IL SQVSFWL NRESVPARTV FGVTTVLTMT TLSISARNSL PKVAYATAMD WFIAVCYAFV FSALIEFATV NYFTKSQPAR AAK IDRLSR IAFPLLFGIF NLVYWATYLN REPQLKAPTP HQ

UniProtKB: Gamma-aminobutyric acid receptor subunit alpha-1, Gamma-aminobutyric acid receptor subunit alpha-1

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Macromolecule #3: Gamma-aminobutyric acid receptor subunit gamma-2

MacromoleculeName: Gamma-aminobutyric acid receptor subunit gamma-2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.673109 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: WSHPQFEKGG GSGGGSGGSS AWSHPQFEKL EVLFQGPQKS DDDYEDYASN KTWVLTPKVP EGDVTVILNN LLEGYDNKLR PDIGVKPTL IHTDMYVNSI GPVNAINMEY TIDIFFAQTW YDRRLKFNST IKVLRLNSNM VGKIWIPDTF FRNSKKADAH W ITTPNRML ...String:
WSHPQFEKGG GSGGGSGGSS AWSHPQFEKL EVLFQGPQKS DDDYEDYASN KTWVLTPKVP EGDVTVILNN LLEGYDNKLR PDIGVKPTL IHTDMYVNSI GPVNAINMEY TIDIFFAQTW YDRRLKFNST IKVLRLNSNM VGKIWIPDTF FRNSKKADAH W ITTPNRML RIWNDGRVLY TLRLTIDAEC QLQLHNFPMD EHSCPLEFSS YGYPREEIVY QWKRSSVEVG DTRSWRLYQF SF VGLRNTT EVVKTTSGDY VVMSVYFDLS RRMGYFTIQT YIPCTLIVVL SWVSFWINKD AVPARTSLGI TTVLTMTTLS TIA RKSLPK VSYVTAMDLF VSVCFIFVFS ALVEYGTLHY FVSSQPARAA KMDSYARIFF PTAFCLFNLV YWVSYLYLSR GSGA TNFSL LKQAGDVEEN PG

UniProtKB: Gamma-aminobutyric acid receptor subunit gamma-2, Gamma-aminobutyric acid receptor subunit gamma-2

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Macromolecule #4: Kappa Fab Light Chain

MacromoleculeName: Kappa Fab Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.505943 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NIVMTQSPKS MSMSVGERVT LSCKASEYVG TYVSWYQQKP EQSPKLLIYG ASNRYTGVPD RFTGSGSATD FTLTIGSVQA EDLADYHCG QSYSYPTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String:
NIVMTQSPKS MSMSVGERVT LSCKASEYVG TYVSWYQQKP EQSPKLLIYG ASNRYTGVPD RFTGSGSATD FTLTIGSVQA EDLADYHCG QSYSYPTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC

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Macromolecule #5: IgG2b Fab Heavy Chain

MacromoleculeName: IgG2b Fab Heavy Chain / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 49.811043 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYMYWVKQR PEQGLEWIGR IDPANGDTKY DPKFQGKATI TTDTFSNTAY LQLSSLTSE DTAVYYCARK GLRWAMDYWG QGTSVTVSTA KTTPPSVYPL APGCGDTTGS SVTLGCLVKG YFPESVTVTW N SGSLSSSV ...String:
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYMYWVKQR PEQGLEWIGR IDPANGDTKY DPKFQGKATI TTDTFSNTAY LQLSSLTSE DTAVYYCARK GLRWAMDYWG QGTSVTVSTA KTTPPSVYPL APGCGDTTGS SVTLGCLVKG YFPESVTVTW N SGSLSSSV HTFPALLQSG LYTMSSSVTV PSSTWPSQTV TCSVAHPASS TTVDKKLEPS GPISTINPCP PCKECHKCPA PN LEGGPSV FIFPPNIKDV LMISLTPKVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ THREDYNSTI RVVSTLPIQH QDW MSGKEF KCKVNNKDLP SPIERTISKI KGLVRAPQVY ILPPPAEQLS RKDVSLTCLV VGFNPGDISV EWTSNGHTEE NYKD TAPVL DSDGSYFIYS KLNMKTSKWE KTDSFSCNVR HEGLKNYYLK KTISRSPGK

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 2 / 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 #10: allopregnanolone

MacromoleculeName: allopregnanolone / type: ligand / ID: 10 / Number of copies: 2 / Formula: Y4B
Molecular weightTheoretical: 318.493 Da
Chemical component information

ChemComp-Y4B:
allopregnanolone

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Macromolecule #11: GAMMA-AMINO-BUTANOIC ACID

MacromoleculeName: GAMMA-AMINO-BUTANOIC ACID / type: ligand / ID: 11 / Number of copies: 2 / Formula: ABU
Molecular weightTheoretical: 103.12 Da
Chemical component information

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM / Γ-Aminobutyric acid

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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

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: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 20.0 µm / Nominal defocus min: 8.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6x3v

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 167534

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