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- EMDB-53260: Inward-occluded structure of human GABA transporter 3 bound to su... -

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Basic information

Entry
Database: EMDB / ID: EMD-53260
TitleInward-occluded structure of human GABA transporter 3 bound to substrate GABA
Map dataCryo-EM map
Sample
  • Complex: Human GABA transporter 3 bound to substrate GABA
    • Protein or peptide: Sodium- and chloride-dependent GABA transporter 3
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsTransport protein / SLC6A11 / neurotransmitter/sodium symporter / Sodium- and chloride-dependent GABA transporter 3 / GAT3 / MEMBRANE PROTEIN
Function / homology
Function and homology information


gamma-aminobutyric acid reuptake / Reuptake of GABA / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / Creatine metabolism / taurine:sodium symporter activity / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / amino acid binding / amino acid transport ...gamma-aminobutyric acid reuptake / Reuptake of GABA / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / Creatine metabolism / taurine:sodium symporter activity / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / amino acid binding / amino acid transport / cell projection / sodium ion transmembrane transport / GABA-ergic synapse / presynaptic membrane / postsynaptic membrane / response to xenobiotic stimulus / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, GABA, GAT-3 / Sodium:neurotransmitter symporter family signature 2. / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile.
Similarity search - Domain/homology
Sodium- and chloride-dependent GABA transporter 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMortensen JS / Bavo F / Jensen MH / Pedersen APS / Storm JP / Pape T / Frolund B / Wellendorph P / Shahsavar A
Funding support Denmark, 4 items
OrganizationGrant numberCountry
LundbeckfondenR368-2021-522 Denmark
Novo Nordisk FoundationNNF21OC0067835 Denmark
Novo Nordisk FoundationNFF20OC0065017 Denmark
Other government1026-00335B Denmark
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for selective inhibition of human GABA transporter GAT3.
Authors: Jonas Sigurd Mortensen / Francesco Bavo / Malene Hall Jensen / Alexander Peder Smiszek Pedersen / Julian Philipp Storm / Tillmann Pape / Bente Frølund / Petrine Wellendorph / Azadeh Shahsavar /
Abstract: The astrocytic γ-aminobutyric acid (GABA) transporter, GAT3, is essential for terminating GABAergic signaling in the central nervous system. Selective inhibition of GAT3 offers a potential strategy ...The astrocytic γ-aminobutyric acid (GABA) transporter, GAT3, is essential for terminating GABAergic signaling in the central nervous system. Selective inhibition of GAT3 offers a potential strategy for elevating extracellular GABA levels for the treatment of neurological disorders including epilepsy. However, few potent and selective GAT3 inhibitors have been developed, and their mechanisms of inhibition remain poorly understood. Here, we present the cryo-electron microscopy structures of full-length, wild-type human GAT3, hGAT3, bound to a selective inhibitor, to substrate GABA, or in substrate-free state. hGAT3 bound to the inhibitor or in the substrate-free state exhibits an inward-open conformation. The inhibitor binds within the intracellular permeation pathway, positioned between transmembrane helices 1, 2, 3, 6, 7, and 8. The GABA-bound hGAT3 is captured in an inward-occluded state, revealing the ion coordination and substrate recognition network, including a cation-π interaction between GABA's γ-amino group and a phenylalanine residue in transmembrane helix 6. Our data reveal the molecular determinants for the inhibitor selectivity, and the mode of substrate binding and transport inhibition, providing blueprints for the rational design of next-generation selective GAT3 inhibitors.
History
DepositionMar 25, 2025-
Header (metadata) releaseMar 4, 2026-
Map releaseMar 4, 2026-
UpdateMar 4, 2026-
Current statusMar 4, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53260.png

Downloads & links

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Map

FileDownload / File: emd_53260.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.57 Å/pix.
x 360 pix.
= 205.56 Å		0.57 Å/pix.
x 360 pix.
= 205.56 Å		0.57 Å/pix.
x 360 pix.
= 205.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.571 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.24998058 - 0.41874993
Average (Standard dev.)0.00051975425 (±0.009319755)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 205.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: EM half map A

Fileemd_53260_half_map_1.map
AnnotationEM half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: EM half map B

Fileemd_53260_half_map_2.map
AnnotationEM half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human GABA transporter 3 bound to substrate GABA

EntireName: Human GABA transporter 3 bound to substrate GABA
Components
  • Complex: Human GABA transporter 3 bound to substrate GABA
    • Protein or peptide: Sodium- and chloride-dependent GABA transporter 3
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: Human GABA transporter 3 bound to substrate GABA

SupramoleculeName: Human GABA transporter 3 bound to substrate GABA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70 KDa

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Macromolecule #1: Sodium- and chloride-dependent GABA transporter 3

MacromoleculeName: Sodium- and chloride-dependent GABA transporter 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.660438 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTAEKALPLG NGKAAEEARE SEAPGGGCSS GGAAPARHPR VKRDKAVHER GHWNNKVEFV LSVAGEIIGL GNVWRFPYLC YKNGGGAFL IPYVVFFICC GIPVFFLETA LGQFTSEGGI TCWRKVCPLF EGIGYATQVI EAHLNVYYII ILAWAIFYLS N CFTTELPW ...String:
MTAEKALPLG NGKAAEEARE SEAPGGGCSS GGAAPARHPR VKRDKAVHER GHWNNKVEFV LSVAGEIIGL GNVWRFPYLC YKNGGGAFL IPYVVFFICC GIPVFFLETA LGQFTSEGGI TCWRKVCPLF EGIGYATQVI EAHLNVYYII ILAWAIFYLS N CFTTELPW ATCGHEWNTE NCVEFQKLNV SNYSHVSLQN ATSPVMEFWE HRVLAISDGI EHIGNLRWEL ALCLLAAWTI CY FCIWKGT KSTGKVVYVT ATFPYIMLLI LLIRGVTLPG ASEGIKFYLY PDLSRLSDPQ VWVDAGTQIF FSYAICLGCL TAL GSYNNY NNNCYRDCIM LCCLNSGTSF VAGFAIFSVL GFMAYEQGVP IAEVAESGPG LAFIAYPKAV TMMPLSPLWA TLFF MMLIF LGLDSQFVCV ESLVTAVVDM YPKVFRRGYR RELLILALSV ISYFLGLVML TEGGMYIFQL FDSYAASGMC LLFVA IFEC ICIGWVYGSN RFYDNIEDMI GYRPPSLIKW CWMIMTPGIC AGIFIFFLIK YKPLKYNNIY TYPAWGYGIG WLMALS SML CIPLWICITV WKTEGTLPEK LQKLTTPSTD LKMRGKLGVS PRMVTVNDCD AKLKSDGTIA AITEKETHF

UniProtKB: Sodium- and chloride-dependent GABA transporter 3

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Macromolecule #2: GAMMA-AMINO-BUTANOIC ACID

MacromoleculeName: GAMMA-AMINO-BUTANOIC ACID / type: ligand / ID: 2 / Number of copies: 1 / Formula: ABU
Molecular weightTheoretical: 103.12 Da
Chemical component information

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

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Macromolecule #3: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration4.00 mg/mL
BufferpH: 7.5
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 180 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 21010 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 215000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1229759
CTF correctionType: NONE
Startup modelType of model: OTHER / Details: AF-P48066-F1-v4
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 96516
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1-v4


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-9qo9:
Inward-occluded structure of human GABA transporter 3 bound to substrate GABA

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