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- EMDB-43512: CryoEM structure of human GABAA receptor pi (GABRP) apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-43512
TitleCryoEM structure of human GABAA receptor pi (GABRP) apo state
Map datasharpened cryo-EM map of GABRP in SMALP200.
Sample
  • Organelle or cellular component: pentameric GABAA receptor pi subunit (GABRP)
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit pi
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCryo-EM / GABAA receptor / Channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / chloride channel complex / chloride transmembrane transport / apical plasma membrane / plasma membrane
Similarity search - Function
Gamma-aminobutyric-acid A receptor pi 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 ...Gamma-aminobutyric-acid A receptor pi 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 pi
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsWang Y / Klein D
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Mol Cell / Year: 2025
Title: GABA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway.
Authors: Yueyue Wang / Yalan Zhang / Wenxue Li / Barbora Salovska / Jianan Zhang / Tongqing Li / Hengyi Li / Yansheng Liu / Leonard K Kaczmarek / Lajos Pusztai / Daryl E Klein /
Abstract: The rare γ-aminobutyric acid type-A receptor (GABAR) subunit π (GABRP) is highly expressed in certain cancers, where it stimulates growth through extracellular-regulated kinase (ERK) signaling by ...The rare γ-aminobutyric acid type-A receptor (GABAR) subunit π (GABRP) is highly expressed in certain cancers, where it stimulates growth through extracellular-regulated kinase (ERK) signaling by an uncharacterized pathway. To elucidate GABRP's signaling mechanism, we determined cryoelectron microscopy (cryo-EM) structures of GABRP embedded in native nanodiscs, both in the presence and absence of GABA. Structurally, GABRP homopentamers closely resemble heteropentameric GABAR anion channels, transitioning from a closed "resting" state to an open "active" state upon GABA binding. However, functional assays reveal that GABRP responds more like a type-B metabotropic receptor. At physiological concentrations of GABA, chloride flux is not detected. Rather, GABRP activates a G-protein-coupled pathway leading to ERK signaling. Ionotropic activity is only triggered at supraphysiological GABA concentrations, effectively decoupling it from GABRP's signaling functions. These findings provide a structural and functional blueprint for GABRP, opening new avenues for targeted inhibition of GABA growth signals in GABRP-positive cancers.
History
DepositionJan 25, 2024-
Header (metadata) releaseDec 11, 2024-
Map releaseDec 11, 2024-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43512.png

Downloads & links

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Map

FileDownload / File: emd_43512.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened cryo-EM map of GABRP in SMALP200.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 247.5 Å		0.83 Å/pix.
x 300 pix.
= 247.5 Å		0.83 Å/pix.
x 300 pix.
= 247.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-1.496026 - 1.9704814
Average (Standard dev.)0.0037579045 (±0.039098646)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 247.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A of GABRP.

Fileemd_43512_half_map_1.map
AnnotationHalf_map_A of GABRP.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of GABRP.

Fileemd_43512_half_map_2.map
AnnotationHalf_map_B of GABRP.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : pentameric GABAA receptor pi subunit (GABRP)

EntireName: pentameric GABAA receptor pi subunit (GABRP)
Components
  • Organelle or cellular component: pentameric GABAA receptor pi subunit (GABRP)
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit pi
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: pentameric GABAA receptor pi subunit (GABRP)

SupramoleculeName: pentameric GABAA receptor pi subunit (GABRP) / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gamma-aminobutyric acid receptor subunit pi

MacromoleculeName: Gamma-aminobutyric acid receptor subunit pi / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.685934 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MNYSLHLAFV CLSLFTERMC IQGSQFNVEV GRSDKLSLPG FENLTAGYNK FLRPNFGGEP VQIALTLDIA SISSISESNM DYTATIYLR QRWMDQRLVF EGNKSFTLDA RLVEFLWVPD TYIVESKKSF LHEVTVGNRL IRLFSNGTVL YALRITTTVA C NMDLSKYP ...String:
MNYSLHLAFV CLSLFTERMC IQGSQFNVEV GRSDKLSLPG FENLTAGYNK FLRPNFGGEP VQIALTLDIA SISSISESNM DYTATIYLR QRWMDQRLVF EGNKSFTLDA RLVEFLWVPD TYIVESKKSF LHEVTVGNRL IRLFSNGTVL YALRITTTVA C NMDLSKYP MDTQTCKLQL ESWGYDGNDV EFTWLRGNDS VRGLEHLRLA QYTIERYFTL VTRSQQETGN YTRLVLQFEL RR NVLYFIL ETYVPSTFLV VLSWVSFWIS LDSVPARTCI GVTTVLSMTT LMIGSRTSLP NTNCFIKAID VYLGICFSFV FGA LLEYAV AHYSSLQQMA AKDRGTTKEV EEVSITNIIN SSISSFKRKI SFASIEISSD NVDYSDLTMK TSDKFKFVFR EKMG RIVDY FTIQNPSNVD HYSKLLFPLI FMLANVFYWA YYMYF

UniProtKB: Gamma-aminobutyric acid receptor subunit pi

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 65740
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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