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- EMDB-38851: Cryo-EM structure of human dopamine transporter in complex with d... -

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Basic information

Entry
Database: EMDB / ID: EMD-38851
TitleCryo-EM structure of human dopamine transporter in complex with dopamine
Map data
Sample
  • Complex: human dopamine transporter in complex with dopamine
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: L-DOPAMINE
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
  • Ligand: water
Keywordshuman dopamine transporter in complex with dopamine / MEMBRANE PROTEIN
Function / homology
Function and homology information


Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / adenohypophysis development / dopamine uptake / hyaloid vascular plexus regression / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity ...Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / adenohypophysis development / dopamine uptake / hyaloid vascular plexus regression / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / neurotransmitter transmembrane transporter activity / regulation of dopamine metabolic process / dopamine transport / flotillin complex / dopamine catabolic process / monoamine transmembrane transporter activity / monoamine transport / dopaminergic synapse / positive regulation of multicellular organism growth / SLC-mediated transport of neurotransmitters / heterocyclic compound binding / response to iron ion / dopamine biosynthetic process / neurotransmitter transport / dopamine uptake involved in synaptic transmission / amino acid transport / response to cAMP / prepulse inhibition / lactation / axon terminus / sodium ion transmembrane transport / protein phosphatase 2A binding / response to nicotine / response to cocaine / locomotory behavior / cognition / sensory perception of smell / presynaptic membrane / protease binding / response to ethanol / postsynaptic membrane / neuron projection / membrane raft / response to xenobiotic stimulus / signaling receptor binding / axon / neuronal cell body / protein-containing complex binding / cell surface / metal ion binding / 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: 2.8 Å
AuthorsZhao Y / Li Y
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nature / Year: 2024
Title: Dopamine reuptake and inhibitory mechanisms in human dopamine transporter.
Authors: Yue Li / Xianping Wang / Yufei Meng / Tuo Hu / Jun Zhao / Renjie Li / Qinru Bai / Pu Yuan / Jun Han / Kun Hao / Yiqing Wei / Yunlong Qiu / Na Li / Yan Zhao /
Abstract: The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. ...The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction.
History
DepositionJan 25, 2024-
Header (metadata) releaseAug 14, 2024-
Map releaseAug 14, 2024-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38851.png

Downloads & links

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Map

FileDownload / File: emd_38851.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: 0.382
Minimum - Maximum-1.5419065 - 2.3547144
Average (Standard dev.)0.00057943043 (±0.06794965)
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_38851_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_38851_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 : human dopamine transporter in complex with dopamine

EntireName: human dopamine transporter in complex with dopamine
Components
  • Complex: human dopamine transporter in complex with dopamine
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: L-DOPAMINE
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
  • Ligand: water

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Supramolecule #1: human dopamine transporter in complex with dopamine

SupramoleculeName: human dopamine transporter in complex with dopamine / 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: 61.348172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DFLLSVIGFA VDLANVWRFP YLCYKNGGGA FLVPYLLFMV IAGMPLFYME LALGQFNREG AAGVWKICPI LKGVGFTVIL ISLYVGFFY NVIIAWALHY LFSSFTTELP WIHCNNSWNS PNCSDAHPGD SSGDSSGLND TFGTTPAAEY FERGVLHLHQ S HGIDDLGP ...String:
DFLLSVIGFA VDLANVWRFP YLCYKNGGGA FLVPYLLFMV IAGMPLFYME LALGQFNREG AAGVWKICPI LKGVGFTVIL ISLYVGFFY NVIIAWALHY LFSSFTTELP WIHCNNSWNS PNCSDAHPGD SSGDSSGLND TFGTTPAAEY FERGVLHLHQ S HGIDDLGP PRWQLTACLV LVIVLLYFSL WKGVKTSGKV VWITATMPYV VLTALLLRGV TLPGAIDGIR AYLSVDFYRL CE ASVWIDA ATQVCFSLGV GFGVLIAFSS YNKFTNNCYR DAIVTTSINS LTSFSSGFVV FSFLGYMAQK HSVPIGDVAK DGP GLIFII YPEAIATLPL SSAWAVVFFI MLLTLGIDSA MGGMESVITG LIDEFQLLHR HRELFTLFIV LATFLLSLFC VTNG GIYVF TLLDHFAAGT SILFGVLIEA IGVAWFYGVG QFSDDIQQMT GQRPSLYWRL CWKLVSPCFL LFVVVVSIVT FRPPH YGAY IFPDWANALG WVIATSSMAM VPIYAAYKFC SLPGSFREKL AYAIAPEKDR ELVDRGEVRQ FTLRHWLKV

UniProtKB: Sodium-dependent dopamine transporter

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Macromolecule #2: L-DOPAMINE

MacromoleculeName: L-DOPAMINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: LDP
Molecular weightTheoretical: 153.178 Da
Chemical component information

ChemComp-LDP:
L-DOPAMINE / medication*YM

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Macromolecule #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #4: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 4 / 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

MicroscopeFEI TITAN 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: 2.2 µm / Nominal defocus min: 1.2 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 213969
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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