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- PDB-9vwr: Cryo-EM structure of human noradrenaline transporter in complex w... -

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Basic information

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


neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / SLC-mediated transport of neurotransmitters / neuron cellular homeostasis / dopamine uptake involved in synaptic transmission ...neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / SLC-mediated transport of neurotransmitters / neuron cellular homeostasis / dopamine uptake involved in synaptic transmission / neuronal cell body membrane / neurotransmitter transport / amino acid transport / alpha-tubulin binding / beta-tubulin binding / sodium ion transmembrane transport / synaptic vesicle membrane / actin binding / chemical synaptic transmission / presynaptic membrane / response to xenobiotic stimulus / axon / cell surface / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, noradrenaline / 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 noradrenaline transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent noradrenaline transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,1653
Polymers63,8011
Non-polymers3642
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 noradrenaline transporter / Norepinephrine transporter / NET / Solute carrier family 6 member 2


Mass: 63801.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A2, NAT1, NET1, SLC6A5 / Production host: Homo sapiens (human) / References: UniProt: P23975
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: 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
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 noradrenaline 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: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155962 / Symmetry type: POINT
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0054579
ELECTRON MICROSCOPYf_angle_d0.6856250
ELECTRON MICROSCOPYf_dihedral_angle_d5.555605
ELECTRON MICROSCOPYf_chiral_restr0.046698
ELECTRON MICROSCOPYf_plane_restr0.006757

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