[English] 日本語
Yorodumi
- EMDB-43475: Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-43475
TitleHuman GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus methaqualone
Map data
Sample
  • Complex: HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH GABA PLUS METHAQUALONE
    • 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
  • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: 2-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydroxy)phosphoryl]-D-serine
Keywordscomplex / methaqualone / drug modulation / GABAA receptor / MEMBRANE PROTEIN
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 / cochlea development / adult behavior / 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
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: 2.82 Å
AuthorsChojnacka W / Teng J / Kim JJ / Jensen AA / Hibbs RE
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)DA047325 United States
CitationJournal: 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
DepositionJan 19, 2024-
Header (metadata) releaseJun 26, 2024-
Map releaseJun 26, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_43475.png

Downloads & links

-
Map

FileDownload / File: emd_43475.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 288 pix.
= 308.16 Å		1.07 Å/pix.
x 288 pix.
= 308.16 Å		1.07 Å/pix.
x 288 pix.
= 308.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.033572868 - 0.1012329
Average (Standard dev.)0.00022285766 (±0.0031033638)
SymmetrySpace group: 1
Details

EMDB XML:

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

-
Supplemental data

-
Additional map: #1

Fileemd_43475_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_43475_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_43475_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

+
Entire : HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH ...

EntireName: HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH GABA PLUS METHAQUALONE
Components
  • Complex: HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH GABA PLUS METHAQUALONE
    • 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
  • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: 2-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydroxy)phosphoryl]-D-serine

+
Supramolecule #1: HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH ...

SupramoleculeName: HUMAN GABAA RECEPTOR ALPHA1-BETA2-GAMMA2 SUBTYPE IN COMPLEX WITH GABA PLUS METHAQUALONE
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 368.767 KDa

+
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

+
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

+
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

+
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: Spodoptera (butterflies/moths)
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

+
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: Spodoptera (butterflies/moths)
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

+
Macromolecule #9: GAMMA-AMINO-BUTANOIC ACID

MacromoleculeName: GAMMA-AMINO-BUTANOIC ACID / type: ligand / ID: 9 / Number of copies: 2 / Formula: ABU
Molecular weightTheoretical: 103.12 Da
Chemical component information

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

+
Macromolecule #10: 2-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one

MacromoleculeName: 2-methyl-3-(2-methylphenyl)quinazolin-4(3H)-one / type: ligand / ID: 10 / Number of copies: 3 / Formula: A1ADG
Molecular weightTheoretical: 250.295 Da

+
Macromolecule #11: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 11 / Number of copies: 4 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

+
Macromolecule #12: O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydr...

MacromoleculeName: O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydroxy)phosphoryl]-D-serine
type: ligand / ID: 12 / Number of copies: 2 / Formula: Q3G
Molecular weightTheoretical: 764.022 Da
Chemical component information

ChemComp-Q3G:
O-[(R)-[(2S)-2-(hexadecanoyloxy)-3-(octadecanoyloxy)propoxy](hydroxy)phosphoryl]-D-serine / phospholipid*YM

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

+
Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 189247
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more