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- EMDB-37846: Cryo-EM structure of noradrenaline transporter in complex with zi... -
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Open data
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Basic information
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Title | Cryo-EM structure of noradrenaline transporter in complex with ziprasidone | |||||||||
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![]() | noradrenaline transporter / Ziprasidone / STRUCTURAL PROTEIN | |||||||||
Function / homology | ![]() neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / norepinephrine transport / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transport ...neurotransmitter:sodium symporter activity / Defective SLC6A2 causes orthostatic intolerance (OI) / norepinephrine uptake / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / norepinephrine transport / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transport / neurotransmitter transport / dopamine uptake involved in synaptic transmission / response to pain / amino acid transport / neuronal cell body membrane / beta-tubulin binding / alpha-tubulin binding / sodium ion transmembrane transport / neuron cellular homeostasis / presynaptic membrane / actin binding / chemical synaptic transmission / response to xenobiotic stimulus / axon / cell surface / membrane / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Zhao Y / Hu T / Yu Z | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.1 KB 14.1 KB | Display Display | ![]() |
Images | ![]() | 169.9 KB | ||
Filedesc metadata | ![]() | 5.6 KB | ||
Others | ![]() ![]() | 59.5 MB 59.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 940.2 KB | Display | ![]() |
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Full document | ![]() | 939.7 KB | Display | |
Data in XML | ![]() | 12.4 KB | Display | |
Data in CIF | ![]() | 14.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8wtyMC ![]() 8wtuC ![]() 8wtvC ![]() 8wtwC ![]() 8wtxC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_37846_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_37846_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : structure of a protein
Entire | Name: structure of a protein |
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Components |
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-Supramolecule #1: structure of a protein
Supramolecule | Name: structure of a protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 63.8 kDa/nm |
-Macromolecule #1: Sodium-dependent noradrenaline transporter
Macromolecule | Name: Sodium-dependent noradrenaline transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 63.801109 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #2: 5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloranyl-...
Macromolecule | Name: 5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloranyl-1,3-dihydroindol-2-one type: ligand / ID: 2 / Number of copies: 1 / Formula: XEF |
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Molecular weight | Theoretical: 412.936 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination 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 model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 375649 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |