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- PDB-9qo8: Inward-open structure of human GABA transporter 3 bound to select... -

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Basic information

Entry
Database: PDB / ID: 9qo8
TitleInward-open structure of human GABA transporter 3 bound to selective inhibitor SR-THAP
ComponentsSodium- and chloride-dependent GABA transporter 3
KeywordsMEMBRANE PROTEIN / Transport protein / SLC6A11 / neurotransmitter/sodium symporter / Sodium- and chloride-dependent GABA transporter 3 / GAT3
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 / sodium ion transmembrane transport / cell projection / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsMortensen, J.S. / Bavo, F. / Jensen, M.H. / Pedersen, A.P.S. / Storm, J.P. / Pape, T. / Frolund, B. / Wellendorph, P. / Shahsavar, A.
Funding support Denmark, 4items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 18, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium- and chloride-dependent GABA transporter 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,2143
Polymers70,6601
Non-polymers5532
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Sodium- and chloride-dependent GABA transporter 3 / GAT-3 / Solute carrier family 6 member 11


Mass: 70660.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A11, GABT3, GAT3 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P48066
#2: Chemical ChemComp-A1I87 / (2S, 2'R)-2-hydroxy-2-(1-((E)-4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl)pyrrolidin-2'-yl)acetic acid / (2~{S})-2-oxidanyl-2-[(2~{R})-1-[(~{E})-4,4,4-tris(4-methoxyphenyl)but-2-enyl]pyrrolidin-2-yl]ethanoic acid


Mass: 517.613 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H35NO6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human GABA transporter 3 bound to selective inhibitor SR-THAP
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.07 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: Expi293F / Plasmid: pCDNA3.1
Buffer solutionpH: 7.5
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.3 sec. / Electron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 44460
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.2particle selection
2EPU3.6image acquisition
7UCSF ChimeraX1.8model fitting
8ISOLDE1.6model fitting
9Coot0.9.8.6model fitting
11PHENIX1.21.1_5286model refinement
15cryoSPARC4.6.23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 139776 / Symmetry type: POINT
Atomic model buildingAccession code: AF-P48066-F1-v4 / Source name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034424
ELECTRON MICROSCOPYf_angle_d0.6996029
ELECTRON MICROSCOPYf_dihedral_angle_d8.701592
ELECTRON MICROSCOPYf_chiral_restr0.045668
ELECTRON MICROSCOPYf_plane_restr0.007732

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