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- PDB-9vws: Cryo-EM structure of human serotonin transporter in complex with ... -

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Basic information

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


negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / negative regulation of organ growth / serotonin:sodium:chloride symporter activity / : / negative regulation of synaptic transmission, dopaminergic ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / negative regulation of organ growth / serotonin:sodium:chloride symporter activity / : / negative regulation of synaptic transmission, dopaminergic / cellular response to cGMP / brain morphogenesis / enteric nervous system development / sodium ion binding / serotonin uptake / vasoconstriction / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / serotonin binding / SLC-mediated transport of neurotransmitters / antiporter activity / syntaxin-1 binding / negative regulation of neuron differentiation / male mating behavior / neurotransmitter transport / nitric-oxide synthase binding / amino acid transport / membrane depolarization / conditioned place preference / cellular response to retinoic acid / monoatomic cation channel activity / behavioral response to cocaine / positive regulation of cell cycle / endomembrane system / response to nutrient / sodium ion transmembrane transport / circadian rhythm / memory / response to toxic substance / platelet aggregation / integrin binding / actin filament binding / response to estradiol / presynaptic membrane / response to hypoxia / postsynaptic membrane / neuron projection / response to xenobiotic stimulus / endosome membrane / membrane raft / focal adhesion / positive regulation of gene expression / synapse / Golgi apparatus / identical protein binding / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, serotonin, N-terminal / Serotonin (5-HT) neurotransmitter transporter, N-terminus / 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
: / CHOLESTEROL HEMISUCCINATE / Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhao, Y. / Li, Y. / Meng, 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
DepositionJul 17, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 22, 2026Data content type: Primary map / Data content type: Primary 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

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent serotonin transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,2686
Polymers70,3711
Non-polymers8965
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 serotonin transporter / SERT / 5HT transporter / 5HTT / Solute carrier family 6 member 4


Mass: 70371.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A4, HTT, SERT / Production host: Homo sapiens (human) / References: UniProt: P31645
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#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-A1EA1 / (1~{R},2~{R},3~{S},5~{S})-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane / Tesofensine


Mass: 328.277 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H23Cl2NO / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4 / 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 serotonin transporter in complex with tesofensine
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
2PHENIX1.19_4092model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 174344 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024494
ELECTRON MICROSCOPYf_angle_d0.4786136
ELECTRON MICROSCOPYf_dihedral_angle_d4.749609
ELECTRON MICROSCOPYf_chiral_restr0.038693
ELECTRON MICROSCOPYf_plane_restr0.004739

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