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- EMDB-65401: Cryo-EM structure of human serotonin transporter in complex with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-65401
TitleCryo-EM structure of human serotonin transporter in complex with tesofensine
Map data
Sample
  • Complex: Cryo-EM structure of human serotonin transporter in complex with tesofensine
    • Protein or peptide: Sodium-dependent serotonin transporter
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: (1~{R},2~{R},3~{S},5~{S})-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsCryo-EM structure of human serotonin transporter in complex with tesofensine / MEMBRANE PROTEIN
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 / : / negative regulation of synaptic transmission, dopaminergic / serotonin:sodium:chloride symporter activity ...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 / : / negative regulation of synaptic transmission, dopaminergic / serotonin:sodium:chloride symporter activity / cellular response to cGMP / brain morphogenesis / enteric nervous system development / sodium ion binding / vasoconstriction / neurotransmitter transmembrane transporter activity / serotonin uptake / 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 / cellular response to retinoic acid / conditioned place preference / monoatomic cation channel activity / behavioral response to cocaine / positive regulation of cell cycle / response to nutrient / sodium ion transmembrane transport / endomembrane system / circadian rhythm / memory / response to toxic substance / platelet aggregation / integrin binding / actin filament binding / response to estradiol / presynaptic membrane / response to hypoxia / neuron projection / postsynaptic membrane / 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
Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhao Y / Li Y / Meng 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
DepositionJul 17, 2025-
Header (metadata) releaseJul 22, 2026-
Map releaseJul 22, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65401.png

Downloads & links

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Map

FileDownload / File: emd_65401.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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.410662 - 2.0213525
Average (Standard dev.)0.00042125676 (±0.0487422)
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_65401_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_65401_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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

EntireName: Cryo-EM structure of human serotonin transporter in complex with tesofensine
Components
  • Complex: Cryo-EM structure of human serotonin transporter in complex with tesofensine
    • Protein or peptide: Sodium-dependent serotonin transporter
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: (1~{R},2~{R},3~{S},5~{S})-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane
  • Ligand: CHOLESTEROL HEMISUCCINATE

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

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

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Macromolecule #1: Sodium-dependent serotonin transporter

MacromoleculeName: Sodium-dependent serotonin transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.371305 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METTPLNSQK QLSACEDGED CQENGVLQKV VPTPGDKVES GQISNGYSAV PSPGAGDDTR HSIPATTTTL VAELHQGERE TWGKKVDFL LSVIGYAVDL GNVWRFPYIC YQNGGGAFLL PYTIMAIFGG IPLFYMELAL GQYHRNGCIS IWRKICPIFK G IGYAICII ...String:
METTPLNSQK QLSACEDGED CQENGVLQKV VPTPGDKVES GQISNGYSAV PSPGAGDDTR HSIPATTTTL VAELHQGERE TWGKKVDFL LSVIGYAVDL GNVWRFPYIC YQNGGGAFLL PYTIMAIFGG IPLFYMELAL GQYHRNGCIS IWRKICPIFK G IGYAICII AFYIASYYNT IMAWALYYLI SSFTDQLPWT SCKNSWNTGN CTNYFSEDNI TWTLHSTSPA EEFYTRHVLQ IH RSKGLQD LGGISWQLAL CIMLIFTVIY FSIWKGVKTS GKVVWVTATF PYIILSVLLV RGATLPGAWR GVLFYLKPNW QKL LETGVW IDAAAQIFFS LGPGFGVLLA FASYNKFNNN CYQDALVTSV VNCMTSFVSG FVIFTVLGYM AEMRNEDVSE VAKD AGPSL LFITYAEAIA NMPASTFFAI IFFLMLITLG LDSTFAGLEG VITAVLDEFP HVWAKRRERF VLAVVITCFF GSLVT LTFG GAYVVKLLEE YATGPAVLTV ALIEAVAVSW FYGITQFCRD VKEMLGFSPG WFWRICWVAI SPLFLLFIIC SFLMSP PQL RLFQYNYPYW SIILGYCIGT SSFICIPTYI AYRLIITPGT FKERIIKSIT PETPTEIPCG DIRLNAV

UniProtKB: Sodium-dependent serotonin transporter

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Macromolecule #2: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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: (1~{R},2~{R},3~{S},5~{S})-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)...

MacromoleculeName: (1~{R},2~{R},3~{S},5~{S})-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1EA1
Molecular weightTheoretical: 328.277 Da

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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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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:

7lia

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 174344
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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