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- EMDB-61180: Cryo-EM structure of human dopamine transporter in complex with d... -

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Basic information

Entry
Database: EMDB / ID: EMD-61180
TitleCryo-EM structure of human dopamine transporter in complex with dasotraline
Map data
Sample
  • Complex: Cryo-EM structure of human dopamine transporter in complex with dasotraline
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: (1~{R},4~{S})-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
  • Ligand: CHLORIDE ION
  • Ligand: CHOLESTEROL
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water
KeywordsCryo-EM structure of human dopamine transporter in complex with dasotraline / MEMBRANE PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhao Y / Li Y
Funding support China, 1 items
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, 2024-
Header (metadata) releaseMar 4, 2026-
Map releaseMar 4, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61180.png

Downloads & links

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Map

FileDownload / File: emd_61180.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.742605 - 1.90639
Average (Standard dev.)0.000106433865 (±0.04877297)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61180_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61180_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of human dopamine transporter in complex with d...

EntireName: Cryo-EM structure of human dopamine transporter in complex with dasotraline
Components
  • Complex: Cryo-EM structure of human dopamine transporter in complex with dasotraline
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: (1~{R},4~{S})-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
  • Ligand: CHLORIDE ION
  • Ligand: CHOLESTEROL
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water

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Supramolecule #1: Cryo-EM structure of human dopamine transporter in complex with d...

SupramoleculeName: Cryo-EM structure of human dopamine transporter in complex with dasotraline
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium-dependent dopamine transporter

MacromoleculeName: Sodium-dependent dopamine transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.465449 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DRETWGKKID FLLSVIGFAV DLANVWRFPY LCYKNGGGAF LVPYLLFMVI AGMPLFYMEL ALGQFNREGA AGVWKICPIL KGVGFTVIL ISLYVGFFYN VIIAWALHYL FSSFTTELPW IHCNNSWNSP NCSDAHPGDS SGDSSGLNDT FGTTPAAEYF E RGVLHLHQ ...String:
DRETWGKKID FLLSVIGFAV DLANVWRFPY LCYKNGGGAF LVPYLLFMVI AGMPLFYMEL ALGQFNREGA AGVWKICPIL KGVGFTVIL ISLYVGFFYN VIIAWALHYL FSSFTTELPW IHCNNSWNSP NCSDAHPGDS SGDSSGLNDT FGTTPAAEYF E RGVLHLHQ SHGIDDLGPP RWQLTACLVL VIVLLYFSLW KGVKTSGKVV WITATMPYVV LTALLLRGVT LPGAIDGIRA YL SVDFYRL CEASVWIDAA TQVCFSLGVG FGVLIAFSSY NKFTNNCYRD AIVTTSINSL TSFSSGFVVF SFLGYMAQKH SVP IGDVAK DGPGLIFIIY PEAIATLPLS SAWAVVFFIM LLTLGIDSAM GGMESVITGL IDEFQLLHRH RELFTLFIVL ATFL LSLFC VTNGGIYVFT LLDHFAAGTS ILFGVLIEAI GVAWFYGVGQ FSDDIQQMTG QRPSLYWRLC WKLVSPCFLL FVVVV SIVT FRPPHYGAYI FPDWANALGW VIATSSMAMV PIYAAYKFCS LPGSFREKLA YAIAPEKDRE LVDRGEVRQF TLRHWL KV

UniProtKB: Sodium-dependent dopamine transporter

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Macromolecule #2: (1~{R},4~{S})-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen...

MacromoleculeName: (1~{R},4~{S})-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EA0
Molecular weightTheoretical: 292.203 Da

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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: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 1 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8y2g

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.7.0) / Number images used: 127813
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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