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- EMDB-33672: Cryo-EM structure of human GABA transporter GAT1 bound with GABA ... -

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Basic information

Entry
Database: EMDB / ID: EMD-33672
TitleCryo-EM structure of human GABA transporter GAT1 bound with GABA in NaCl solution in an inward-occluded state at 2.4 angstrom
Map data
Sample
  • Complex: GAT1
    • Protein or peptide: Sodium- and chloride-dependent GABA transporter 1
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
  • Ligand: water
KeywordsGABA transporter / GAT1 / Nipecotic acid / Tiagabine / Neurotransmitter / SLC6A1. / TRANSPORT PROTEIN
Function / homology
Function and homology information


gamma-aminobutyric acid reuptake / Reuptake of GABA / inorganic anion import across plasma membrane / sodium:chloride symporter activity / gamma-aminobutyric acid transmembrane transporter activity / gamma-aminobutyric acid import / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / sodium ion import across plasma membrane / amino acid transport ...gamma-aminobutyric acid reuptake / Reuptake of GABA / inorganic anion import across plasma membrane / sodium:chloride symporter activity / gamma-aminobutyric acid transmembrane transporter activity / gamma-aminobutyric acid import / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / sodium ion import across plasma membrane / amino acid transport / associative learning / transport across blood-brain barrier / sodium ion transmembrane transport / chloride transmembrane transport / synapse organization / GABA-ergic synapse / memory / presynapse / chemical synaptic transmission / axon / neuronal cell body / cell surface / metal ion binding / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, GABA, GAT-1 / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsZhu A / Huang J / Kong F / Tan J / Lei J / Yuan Y / Yan C
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509301 China
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Molecular basis for substrate recognition and transport of human GABA transporter GAT1.
Authors: Angqi Zhu / Junhao Huang / Fang Kong / Jiaxin Tan / Jianlin Lei / Yafei Yuan / Chuangye Yan /
Abstract: γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the ...γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2-3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine.
History
DepositionJun 22, 2022-
Header (metadata) releaseApr 26, 2023-
Map releaseApr 26, 2023-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33672.png

Downloads & links

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Map

FileDownload / File: emd_33672.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 200 pix.
= 216.5 Å		1.08 Å/pix.
x 200 pix.
= 216.5 Å		1.08 Å/pix.
x 200 pix.
= 216.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-2.7314835 - 4.5481334
Average (Standard dev.)0.0020434042 (±0.098014764)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 216.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33672_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33672_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : GAT1

EntireName: GAT1
Components
  • Complex: GAT1
    • Protein or peptide: Sodium- and chloride-dependent GABA transporter 1
  • Ligand: GAMMA-AMINO-BUTANOIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
  • Ligand: water

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Supramolecule #1: GAT1

SupramoleculeName: GAT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 110 KDa

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

MacromoleculeName: Sodium- and chloride-dependent GABA transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.895898 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATNGSKVAD GQISTEVSEA PVANDKPKTL VVKVQKKAAD LPDRDTWKGR FDFLMSCVGY AIGLGNVWRF PYLCGKNGGG AFLIPYFLT LIFAGVPLFL LECSLGQYTS IGGLGVWKLA PMFKGVGLAA AVLSFWLNIY YIVIISWAIY YLYNSFTTTL P WKQCDNPW ...String:
MATNGSKVAD GQISTEVSEA PVANDKPKTL VVKVQKKAAD LPDRDTWKGR FDFLMSCVGY AIGLGNVWRF PYLCGKNGGG AFLIPYFLT LIFAGVPLFL LECSLGQYTS IGGLGVWKLA PMFKGVGLAA AVLSFWLNIY YIVIISWAIY YLYNSFTTTL P WKQCDNPW NTDRCFSNYS MVNTTNMTSA VVEFWERNMH QMTDGLDKPG QIRWPLAITL AIAWILVYFC IWKGVGWTGK VV YFSATYP YIMLIILFFR GVTLPGAKEG ILFYITPNFR KLSDSEVWLD AATQIFFSYG LGLGSLIALG SYNSFHNNVY RDS IIVCCI NSCTSMFAGF VIFSIVGFMA HVTKRSIADV AASGPGLAFL AYPEAVTQLP ISPLWAILFF SMLLMLGIDS QFCT VEGFI TALVDEYPRL LRNRRELFIA AVCIISYLIG LSNITQGGIY VFKLFDYYSA SGMSLLFLVF FECVSISWFY GVNRF YDNI QEMVGSRPCI WWKLCWSFFT PIIVAGVFIF SAVQMTPLTM GNYVFPKWGQ GVGWLMALSS MVLIPGYMAY MFLTLK GSL KQRIQVMVQP SEDIVRPENG PEQPQAGSST SKEAYILESG DEVDASGDYK DHDGDYKDHD IDYKDDDDK

UniProtKB: Sodium- and chloride-dependent GABA transporter 1

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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

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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: 3 / 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: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 48 / 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

Concentration8 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (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: 1.4000000000000001 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 847882
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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