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- PDB-9j6t: Cryo-EM structure of human dopamine transporter in complex with c... -

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Entry
Database: PDB / ID: 9j6t
TitleCryo-EM structure of human dopamine transporter in complex with centanafadine
ComponentsSodium-dependent dopamine transporter
KeywordsMEMBRANE PROTEIN / Cryo-EM structure of human dopamine transporter in complex with centanafadine
Function / homology
Function and homology information


Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / hyaloid vascular plexus regression / dopamine uptake / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / response to leptin ...Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / hyaloid vascular plexus regression / dopamine uptake / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / response to leptin / neurotransmitter transmembrane transporter activity / flotillin complex / monoamine transmembrane transporter activity / dopaminergic synapse / SLC-mediated transport of neurotransmitters / response to iron ion / heterocyclic compound binding / dopamine uptake involved in synaptic transmission / neurotransmitter transport / amino acid transport / response to cAMP / protein phosphatase 2A binding / axon terminus / response to nicotine / sodium ion transmembrane transport / protease binding / presynaptic membrane / response to ethanol / neuron projection / postsynaptic membrane / response to xenobiotic stimulus / membrane raft / signaling receptor binding / axon / neuronal cell body / protein-containing complex binding / cell surface / membrane / plasma membrane / cytoplasm
Similarity search - Function
Sodium:neurotransmitter symporter, dopamine / 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-dependent dopamine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhao, Y. / Li, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for pharmacotherapeutic action of triple reuptake inhibitors.
Authors: Yue Li / Yufei Meng / Na Li / Jun Zhao / Renjie Li / Qinru Bai / Gang Wang / Yan Zhao /
Abstract: Most first-line pharmacotherapeutic strategies for depression aim to boost serotonin and norepinephrine levels. However, 35% of patients with depression do not respond adequately to these treatments ...Most first-line pharmacotherapeutic strategies for depression aim to boost serotonin and norepinephrine levels. However, 35% of patients with depression do not respond adequately to these treatments or experience adverse side effects. The serotonin-norepinephrine-dopamine reuptake inhibitors, also known as triple reuptake inhibitors (TRIs), are emerging as promising antidepressants with greater potency and fewer side effects. Here, we determine an ensemble of structures of DAT in complex with five distinct TRIs. Tesofensine and dasotraline stabilize DAT in an outward-facing conformation, while centanafadine, ansofaxine, and nefazodone capture the inward-facing conformation. These structures reveal binding poses and interactions involved in the association of inhibitors. Notably, ansofaxine binds at a location which is much closer to the intracellular membrane surface. Through extensive structural analysis, we establish a comprehensive blueprint for the association of these TRIs, which is crucial for future drug development aimed at achieving potent antidepressant with fewer side effect.
History
DepositionAug 17, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release
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Revision 1.0Mar 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium-dependent dopamine transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0213
Polymers61,5911
Non-polymers4302
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium-dependent dopamine transporter / DA transporter / DAT / Solute carrier family 6 member 3


Mass: 61590.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A3, DAT1 / Production host: Homo sapiens (human) / References: UniProt: Q01959
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-A1EA2 / (1~{R},5~{S})-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane / Centanafadine


Mass: 209.286 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N / Feature type: SUBJECT OF INVESTIGATION
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: Cryo-EM structure of human dopamine transporter in complex with dasotraline
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.7.0particle selection
2cryoSPARCv4.7.0image acquisition
8PHENIXmodel refinement
13cryoSPARCv4.7.03D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 52169 / Symmetry type: POINT
RefinementHighest resolution: 3.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024338
ELECTRON MICROSCOPYf_angle_d0.4925924
ELECTRON MICROSCOPYf_dihedral_angle_d4.059587
ELECTRON MICROSCOPYf_chiral_restr0.037676
ELECTRON MICROSCOPYf_plane_restr0.004722

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