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- EMDB-62281: Cryo-EM structure of LIPID-mediated human norepinephrine transpor... -

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Basic information

Entry
Database: EMDB / ID: EMD-62281
TitleCryo-EM structure of LIPID-mediated human norepinephrine transporter NET in the presence of Levomilnacipran in an inward-open state at resolution of 2.46 angstrom.
Map data
Sample
  • Complex: Sodium-dependent noradrenaline transporter
    • Protein or peptide: Sodium-dependent noradrenaline transporter
  • Ligand: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide
  • Ligand: CHOLESTEROL
  • Ligand: [(2~{R})-1-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-nonanoyloxy-propan-2-yl] decanoate
KeywordsComplex / TRANSPORT PROTEIN
Function / homology
Function and homology information


neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / norepinephrine transport / dopamine:sodium symporter activity / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / monoamine transport / SLC-mediated transport of neurotransmitters ...neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / norepinephrine transport / dopamine:sodium symporter activity / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / monoamine transport / SLC-mediated transport of neurotransmitters / response to pain / neuronal cell body membrane / neurotransmitter transport / dopamine uptake involved in synaptic transmission / amino acid transport / alpha-tubulin binding / beta-tubulin binding / sodium ion transmembrane transport / neuron cellular homeostasis / synaptic vesicle membrane / actin binding / presynaptic membrane / chemical synaptic transmission / response to xenobiotic stimulus / axon / cell surface / metal ion binding / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.46 Å
AuthorsZhang H / Jiang Y / Xu EH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell / Year: 2025
Title: Unveiling conformation-selective regulation of the norepinephrine transporter.
Authors: Heng Zhang / Tianwei Zhang / Dingyan Wang / Antao Dai / Jianhang Mao / Qihui Chen / Tianyuan Du / Xue Lu / Yongxin Hao / Chao Zhang / Yu-Ling Yin / Wen Hu / Benxun Pan / Sanshan Jin / ...Authors: Heng Zhang / Tianwei Zhang / Dingyan Wang / Antao Dai / Jianhang Mao / Qihui Chen / Tianyuan Du / Xue Lu / Yongxin Hao / Chao Zhang / Yu-Ling Yin / Wen Hu / Benxun Pan / Sanshan Jin / Mengting Jiang / Yuan Si / Qingning Yuan / Ming-Wei Wang / Mingyue Zheng / Zhen Wang / Dehua Yang / H Eric Xu / Yi Jiang /
Abstract: The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of ...The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of its allosteric, conformation-selective regulation-crucial for developing targeted therapeutics-remains limited. Through cryo-electron microscopy analysis of NET complexes with levomilnacipran, vanoxerine, and vilazodone, we identify a previously undefined allosteric site within NET's inner vestibule that enables conformation-selective regulation. This discovery introduces a "valve model," in which specific residues partition the cytoplasmic cavity into distinct chambers, determining inhibitor binding specificity. Leveraging this structural insight through virtual screening, we identify a set of inhibitors with potent NET inhibitory activity and demonstrate their antidepressant effects. Moreover, our structural identification of inhibitor occupancy at this conformation-selective site defines a mechanistic framework for targeted therapeutic intervention. These findings advance our understanding of NET allosteric modulation, providing a structure-guided framework for developing next-generation antidepressants targeting the inward-open conformation of NET for the treatment of neuropsychiatric disorders.
History
DepositionNov 3, 2024-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62281.png

Downloads & links

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Map

FileDownload / File: emd_62281.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å		0.73 Å/pix.
x 320 pix.
= 233.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.3591403 - 0.88305736
Average (Standard dev.)0.000095776 (±0.03159809)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 233.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62281_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_62281_half_map_2.map
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Sample components

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Entire : Sodium-dependent noradrenaline transporter

EntireName: Sodium-dependent noradrenaline transporter
Components
  • Complex: Sodium-dependent noradrenaline transporter
    • Protein or peptide: Sodium-dependent noradrenaline transporter
  • Ligand: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide
  • Ligand: CHOLESTEROL
  • Ligand: [(2~{R})-1-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-nonanoyloxy-propan-2-yl] decanoate

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Supramolecule #1: Sodium-dependent noradrenaline transporter

SupramoleculeName: Sodium-dependent noradrenaline transporter / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium-dependent noradrenaline transporter

MacromoleculeName: Sodium-dependent noradrenaline transporter / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.715875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKG SGMLLARMNP QVQPENNGAD TGPEQPLRAR KTAELLVVKE RNGVQCLLAP RDGDAQPRET WGKKIDFLLS VVGFAVDLA NVWRFPYLCY KNGGGAFLIP YTLFLIIAGM PLFYMELALG QYNREGAATV WKICPFFKGV GYAVILIALY V GFYYNVII ...String:
MDYKDDDDKG SGMLLARMNP QVQPENNGAD TGPEQPLRAR KTAELLVVKE RNGVQCLLAP RDGDAQPRET WGKKIDFLLS VVGFAVDLA NVWRFPYLCY KNGGGAFLIP YTLFLIIAGM PLFYMELALG QYNREGAATV WKICPFFKGV GYAVILIALY V GFYYNVII AWSLYYLFSS FTLNLPWTDC GHTWNSPNCT DPKLLNGSVL GNHTKYSKYK FTPAAEFYER GVLHLHESSG IH DIGLPQW QLLLCLMVVV IVLYFSLWKG VKTSGKVVWI TATLPYFVLF VLLVHGVTLP GASNGINAYL HIDFYRLKEA TVW IDAATQ IFFSLGAGFG VLIAFASYNK FDNNCYRDAL LTSSINCITS FVSGFAIFSI LGYMAHEHKV NIEDVATEGA GLVF ILYPE AISTLSGSTF WAVVFFVMLL ALGLDSSMGG MEAVITGLAD DFQVLKRHRK LFTFGVTFST FLLALFCITK GGIYV LTLL DTFAAGTSIL FAVLMEAIGV SWFYGVDRFS NDIQQMMGFR PGLYWRLCWK FVSPAFLLFV VVVSIINFKP LTYDDY IFP PWANWVGWGI ALSSMVLVPI YVIYKFLSTQ GSLWERLAYG ITPENEHHLV AQRDIRQFQL QHWLAI

UniProtKB: Sodium-dependent noradrenaline transporter

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Macromolecule #2: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carbo...

MacromoleculeName: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide
type: ligand / ID: 2 / Number of copies: 2 / Formula: F0F
Molecular weightTheoretical: 246.348 Da
Chemical component information

ChemComp-F0F:
(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 16 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: [(2~{R})-1-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphory...

MacromoleculeName: [(2~{R})-1-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-nonanoyloxy-propan-2-yl] decanoate
type: ligand / ID: 4 / Number of copies: 2 / Formula: A1EFM
Molecular weightTheoretical: 540.624 Da

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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: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 3.0 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 AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.46 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 277385
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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