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- EMDB-37846: Cryo-EM structure of noradrenaline transporter in complex with zi... -

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Basic information

Entry
Database: EMDB / ID: EMD-37846
TitleCryo-EM structure of noradrenaline transporter in complex with ziprasidone
Map data
Sample
  • Complex: structure of a protein
    • Protein or peptide: Sodium-dependent noradrenaline transporter
  • Ligand: Ziprasidone
Keywordsnoradrenaline transporter / Ziprasidone / STRUCTURAL 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 / Na+/Cl- dependent neurotransmitter transporters ...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 / Na+/Cl- dependent neurotransmitter transporters / neurotransmitter transport / neuronal cell body membrane / response to pain / dopamine uptake involved in synaptic transmission / amino acid transport / beta-tubulin binding / alpha-tubulin binding / sodium ion transmembrane transport / neuron cellular homeostasis / synaptic vesicle membrane / presynaptic membrane / actin binding / 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: 3.2 Å
AuthorsZhao Y / Hu T / Yu Z
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030304 China
CitationJournal: Nature / Year: 2024
Title: Transport and inhibition mechanisms of the human noradrenaline transporter.
Authors: Tuo Hu / Zhuoya Yu / Jun Zhao / Yufei Meng / Kristine Salomon / Qinru Bai / Yiqing Wei / Jinghui Zhang / Shujing Xu / Qiuyun Dai / Rilei Yu / Bei Yang / Claus J Loland / Yan Zhao /
Abstract: The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the ...The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons. It is a pharmacological target for various antidepressants and analgesic drugs. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlA), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na and Cl undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlA provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design.
History
DepositionOct 19, 2023-
Header (metadata) releaseAug 7, 2024-
Map releaseAug 7, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37846.png

Downloads & links

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Map

FileDownload / File: emd_37846.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: 0.35
Minimum - Maximum-1.9378284 - 2.2777739
Average (Standard dev.)-0.000011964999 (±0.056141924)
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_37846_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_37846_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : structure of a protein

EntireName: structure of a protein
Components
  • Complex: structure of a protein
    • Protein or peptide: Sodium-dependent noradrenaline transporter
  • Ligand: Ziprasidone

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Supramolecule #1: structure of a protein

SupramoleculeName: structure of a protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.8 kDa/nm

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Macromolecule #1: Sodium-dependent noradrenaline transporter

MacromoleculeName: Sodium-dependent noradrenaline transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.801109 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DAQPRETWGK KIDFLLSVVG FAVDLANVWR FPYLCYKNGG GAFLIPYTLF LIIAGMPLFY MELALGQYNR EGAATVWKIC PFFKGVGYA VILIALYVGF YYNVIIAWSL YYLFSSFTLN LPWTDCGHTW NSPNCTDPKL LNGSVLGNHT KYSKYKFTPA A EFYERGVL ...String:
DAQPRETWGK KIDFLLSVVG FAVDLANVWR FPYLCYKNGG GAFLIPYTLF LIIAGMPLFY MELALGQYNR EGAATVWKIC PFFKGVGYA VILIALYVGF YYNVIIAWSL YYLFSSFTLN LPWTDCGHTW NSPNCTDPKL LNGSVLGNHT KYSKYKFTPA A EFYERGVL HLHESSGIHD IGLPQWQLLL CLMVVVIVLY FSLWKGVKTS GKVVWITATL PYFVLFVLLV HGVTLPGASN GI NAYLHID FYRLKEATVW IDAATQIFFS LGAGFGVLIA FASYNKFDNN CYRDALLTSS INCITSFVSG FAIFSILGYM AHE HKVNIE DVATEGAGLV FILYPEAIST LSGSTFWAVV FFVMLLALGL DSSMGGMEAV ITGLADDFQV LKRHRKLFTF GVTF STFLL ALFCITKGGI YVLTLLDTFA AGTSILFAVL MEAIGVSWFY GVDRFSNDIQ QMMGFRPGLY WRLCWKFVSP AFLLF VVVV SIINFKPLTY DDYIFPPWAN WVGWGIALSS MVLVPIYVIY KFLSTQGSLW ERLAYGITPE NEHHLVAQRD IRQFQL QHW LAI

UniProtKB: Sodium-dependent noradrenaline transporter

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Macromolecule #2: Ziprasidone

MacromoleculeName: Ziprasidone / type: ligand / ID: 2 / Number of copies: 1 / Formula: XEF
Molecular weightTheoretical: 412.936 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

MicroscopeFEI TITAN 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: OTHER / 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

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 375649
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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