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- EMDB-43546: CryoEM structure of human GABAA receptor pi (GABRP) in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-43546
TitleCryoEM structure of human GABAA receptor pi (GABRP) in complex with GABA
Map dataCryo-EM reconstruction map of human pi GABAA receptor in complex with GABA
Sample
  • Organelle or cellular component: pentameric GABAA receptor pi subunit (GABRP) in complex with GABA
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit pi
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
KeywordsCryo-EM / GABAA receptor / Channel / complex / 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: 3.1 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 30, 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_43546.png

Downloads & links

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Map

FileDownload / File: emd_43546.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM reconstruction map of human pi GABAA receptor in complex with GABA
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: 0.135
Minimum - Maximum-1.4245135 - 1.9786297
Average (Standard dev.)0.0038214126 (±0.042191572)
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 B of human pi GABAA receptor in complex with GABA

Fileemd_43546_half_map_1.map
Annotationhalf map B of human pi GABAA receptor in complex with GABA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A of human pi GABAA receptor in complex with GABA

Fileemd_43546_half_map_2.map
Annotationhalf map A of human pi GABAA receptor in complex with GABA
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) in complex with GABA

EntireName: pentameric GABAA receptor pi subunit (GABRP) in complex with GABA
Components
  • Organelle or cellular component: pentameric GABAA receptor pi subunit (GABRP) in complex with GABA
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit pi
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GAMMA-AMINO-BUTANOIC ACID

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Supramolecule #1: pentameric GABAA receptor pi subunit (GABRP) in complex with GABA

SupramoleculeName: pentameric GABAA receptor pi subunit (GABRP) in complex with GABA
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: 43.285105 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SQFNVEVGRS DKLSLPGFEN LTAGYNKFLR PNFGGEPVQI ALTLDIASIS SISESNMDYT ATIYLRQRWM DQRLVFEGNK SFTLDARLV EFLWVPDTYI VESKKSFLHE VTVGNRLIRL FSNGTVLYAL RITTTVACNM DLSKYPMDTQ TCKLQLESWG Y DGNDVEFT ...String:
SQFNVEVGRS DKLSLPGFEN LTAGYNKFLR PNFGGEPVQI ALTLDIASIS SISESNMDYT ATIYLRQRWM DQRLVFEGNK SFTLDARLV EFLWVPDTYI VESKKSFLHE VTVGNRLIRL FSNGTVLYAL RITTTVACNM DLSKYPMDTQ TCKLQLESWG Y DGNDVEFT WLRGNDSVRG LEHLRLAQYT IERYFTLVTR SQQETGNYTR LVLQFELRRN VLYFILETYV PSTFLVVLSW VS FWISLDS VPARTCIGVT TVLSMTTLMI GSRTSLPNTN CFIKAIDVYL GICFSFVFGA LLEYAVAHYS SLSQPARAAN VDH YSKLLF PLIFMLANVF YWAYYMYFEF GGSRGSAWSH PQFEKGGGSG GGSGGSAWSH PQFEK

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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Macromolecule #4: GAMMA-AMINO-BUTANOIC ACID

MacromoleculeName: GAMMA-AMINO-BUTANOIC ACID / type: ligand / ID: 4 / Number of copies: 5 / Formula: ABU
Molecular weightTheoretical: 103.12 Da
Chemical component information

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC 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
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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 62045
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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