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- PDB-8y2d: Cryo-EM structure of human dopamine transporter in complex with d... -

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Basic information

Entry
Database: PDB / ID: 8y2d
TitleCryo-EM structure of human dopamine transporter in complex with dopamine
ComponentsSodium-dependent dopamine transporter
KeywordsMEMBRANE PROTEIN / human dopamine transporter in complex with dopamine
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 / norepinephrine transport / regulation of dopamine metabolic process / neurotransmitter transmembrane transporter activity / dopamine transport / dopaminergic synapse / flotillin complex / 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 / neuronal cell body membrane / 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 / membrane / metal ion binding / 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
L-DOPAMINE / Sodium-dependent dopamine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhao, Y. / Li, Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.2Aug 28, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update
Revision 1.3Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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)61,5835
Polymers61,3481
Non-polymers2354
Water724
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: 61348.172 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: Chemical ChemComp-LDP / L-DOPAMINE / DOPAMINE


Mass: 153.178 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H11NO2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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 dopamine transporter in complex with dopamine / 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 213969 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034312
ELECTRON MICROSCOPYf_angle_d0.4895886
ELECTRON MICROSCOPYf_dihedral_angle_d3.911576
ELECTRON MICROSCOPYf_chiral_restr0.037665
ELECTRON MICROSCOPYf_plane_restr0.004724

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