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- EMDB-38853: structure of a proteinACryo-EM structure of human dopamine transp... -

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Basic information

Entry
Database: EMDB / ID: EMD-38853
Titlestructure of a proteinACryo-EM structure of human dopamine transporter in complex with GBR12909
Map data
Sample
  • Complex: human dopamine transporter in complex with GBR12909
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: Vanoxerine
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordshuman dopamine transporter human dopamine transporter / 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 / regulation of dopamine metabolic process / neurotransmitter transmembrane transporter activity / dopamine transport / flotillin complex / dopaminergic synapse / dopamine catabolic process / monoamine transmembrane transporter activity / monoamine transport / positive regulation of multicellular organism growth / Na+/Cl- dependent neurotransmitter transporters / response to iron ion / dopamine biosynthetic process / neurotransmitter transport / heterocyclic compound binding / dopamine uptake involved in synaptic transmission / amino acid transport / prepulse inhibition / response to cAMP / axon terminus / lactation / sodium ion transmembrane transport / protein phosphatase 2A binding / locomotory behavior / response to nicotine / response to cocaine / cognition / sensory perception of smell / presynaptic membrane / protease binding / response to ethanol / postsynaptic membrane / neuron projection / membrane raft / response to xenobiotic stimulus / axon / signaling receptor binding / 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: 2.97 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-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38853.png

Downloads & links

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Map

FileDownload / File: emd_38853.map.gz / Format: CCP4 / Size: 125 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 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. 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: 0.37
Minimum - Maximum-1.6982499 - 2.1593425
Average (Standard dev.)-0.00045337866 (±0.041650914)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38853_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_38853_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human dopamine transporter in complex with GBR12909

EntireName: human dopamine transporter in complex with GBR12909
Components
  • Complex: human dopamine transporter in complex with GBR12909
    • Protein or peptide: Sodium-dependent dopamine transporter
  • Ligand: Vanoxerine
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: human dopamine transporter in complex with GBR12909

SupramoleculeName: human dopamine transporter in complex with GBR12909 / 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: 61.590508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KIDFLLSVIG FAVDLANVWR FPYLCYKNGG GAFLVPYLLF MVIAGMPLFY MELALGQFNR EGAAGVWKIC PILKGVGFTV ILISLYVGF FYNVIIAWAL HYLFSSFTTE LPWIHCNNSW NSPNCSDAHP GDSSGDSSGL NDTFGTTPAA EYFERGVLHL H QSHGIDDL ...String:
KIDFLLSVIG FAVDLANVWR FPYLCYKNGG GAFLVPYLLF MVIAGMPLFY MELALGQFNR EGAAGVWKIC PILKGVGFTV ILISLYVGF FYNVIIAWAL HYLFSSFTTE LPWIHCNNSW NSPNCSDAHP GDSSGDSSGL NDTFGTTPAA EYFERGVLHL H QSHGIDDL GPPRWQLTAC LVLVIVLLYF SLWKGVKTSG KVVWITATMP YVVLTALLLR GVTLPGAIDG IRAYLSVDFY RL CEASVWI DAATQVCFSL GVGFGVLIAF SSYNKFTNNC YRDAIVTTSI NSLTSFSSGF VVFSFLGYMA QKHSVPIGDV AKD GPGLIF IIYPEAIATL PLSSAWAVVF FIMLLTLGID SAMGGMESVI TGLIDEFQLL HRHRELFTLF IVLATFLLSL FCVT NGGIY VFTLLDHFAA GTSILFGVLI EAIGVAWFYG VGQFSDDIQQ MTGQRPSLYW RLCWKLVSPC FLLFVVVVSI VTFRP PHYG AYIFPDWANA LGWVIATSSM AMVPIYAAYK FCSLPGSFRE KLAYAIAPEK DRELVDRGEV RQFTLRHWLK V

UniProtKB: Sodium-dependent dopamine transporter

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Macromolecule #2: Vanoxerine

MacromoleculeName: Vanoxerine / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1D5S
Molecular weightTheoretical: 450.563 Da

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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: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 182906
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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