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- PDB-8wtw: Cryo-EM structure of noradrenaline transporter in complex with a ... -

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Basic information

Entry
Database: PDB / ID: 8wtw
TitleCryo-EM structure of noradrenaline transporter in complex with a x-MrlA analogue
Components
  • MrlA
  • Sodium-dependent noradrenaline transporter
KeywordsSTRUCTURAL PROTEIN / Norapinephrine transporter / MrlA
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 / neuronal cell body membrane / response to pain / 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)
Conus marmoreus (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhao, Y. / Hu, T. / Yu, Z.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent noradrenaline transporter
B: MrlA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,5495
Polymers65,4672
Non-polymers813
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Sodium-dependent noradrenaline transporter


Mass: 63801.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: This NH2 addition at the C-terminus is a deliberate modification and is consistent with the handling of this peptide based on its homologous counterpart, PDB ID: 2EW4.
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A2 / Production host: Homo sapiens (human) / References: UniProt: P23975
#2: Protein/peptide MrlA


Mass: 1666.069 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Conus marmoreus (invertebrata)
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
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: apo / 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / 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 softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 313089 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024674
ELECTRON MICROSCOPYf_angle_d0.4226371
ELECTRON MICROSCOPYf_dihedral_angle_d4.605612
ELECTRON MICROSCOPYf_chiral_restr0.036707
ELECTRON MICROSCOPYf_plane_restr0.003773

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