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- PDB-9k6x: Structural and functional basis of antinociceptive action of cono... -

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Basic information

Entry
Database: PDB / ID: 9k6x
TitleStructural and functional basis of antinociceptive action of conotoxin AoIA at the noradrenaline transporter
Components
  • Sodium-dependent noradrenaline transporter
  • conotoxin AoIA
KeywordsTRANSPORT PROTEIN / Complex
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 ...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 / presynaptic membrane / chemical synaptic transmission / response to xenobiotic stimulus / axon / cell surface / membrane / metal ion binding / 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
: / CHOLESTEROL / Sodium-dependent noradrenaline transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Conus marmoreus (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsZhang, H. / Harald, S. / Oliver, B. / Xu, E.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter.
Authors: Oliver J V Belleza / Heng Zhang / Helmut Schmidhammer / Tye I Gonzalez / Cosmin I Ciotu / Nataša Tomašević / Carlo Martin M Ocampo / Jomari C Fernando / Johannes Koehbach / Paula Schwarz ...Authors: Oliver J V Belleza / Heng Zhang / Helmut Schmidhammer / Tye I Gonzalez / Cosmin I Ciotu / Nataša Tomašević / Carlo Martin M Ocampo / Jomari C Fernando / Johannes Koehbach / Paula Schwarz / Mounaf Al Makhlouf / Gabor Tajti / Simon Hasinger / Nina Kastner / Orcun Avsar / Bernhard Retzl / Kathrin Jäntsch / Yi Jiang / Roland Hellinger / Michael J M Fischer / K Johan Rosengren / Christian W Gruber / Aaron Joseph L Villaraza / Thomas Stockner / Mariana Spetea / H Eric Xu / Harald H Sitte /
Abstract: The χ-conotoxins are venom-derived peptides that specifically target the noradrenaline transporter (also known as norepinephrine transporter, NET). Regulation of noradrenergic signaling by NET ...The χ-conotoxins are venom-derived peptides that specifically target the noradrenaline transporter (also known as norepinephrine transporter, NET). Regulation of noradrenergic signaling by NET affects neurophysiological processes, including pain. Therefore, the χ-conotoxin MrIA and its synthetic analogs have been previously investigated for their analgesic activity. Here we describe the synthesis and pharmacological characterization of χ-AoIA, a peptide that selectively inhibits NET with a higher potency compared to MrIA in in vitro radiotracer flux assays. Furthermore, we resolved the structure of the human NET:χ-AoIA complex by cryogenic electron microscopy, which revealed an atypical binding mode consisting of both the central binding site and the outer vestibule of the transporter. Lastly, χ-AoIA displays antinociceptive efficacy in a model of inflammatory pain after subcutaneous administration in mice. Our results demonstrate the efficacy of χ-AoIA as a highly selective ligand of NET and provide a mechanistic basis for its potential development as a nonopioid analgesic.
History
DepositionOct 22, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 6, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: conotoxin AoIA
A: Sodium-dependent noradrenaline transporter
B: Sodium-dependent noradrenaline transporter
D: conotoxin AoIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,66426
Polymers144,0714
Non-polymers6,59322
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein/peptide / Protein , 2 types, 4 molecules CDAB

#1: Protein/peptide conotoxin AoIA


Mass: 1319.643 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Conus marmoreus (invertebrata)
#2: Protein Sodium-dependent noradrenaline transporter / Norepinephrine transporter / NET / Solute carrier family 6 member 2


Mass: 70715.875 Da / Num. of mol.: 2
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

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Non-polymers , 4 types, 22 molecules

#3: Chemical ChemComp-A1EET / [(2~{R})-3-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-2-oxidanyl-propyl] (9~{Z},12~{Z})-octadeca-9,12-dienoate / LPG(18:2)


Mass: 508.582 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H45O9P / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C27H46O

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Details

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 norepinephrine transporter NET in an outward-open state in complex with a conotoxin ArXA-B
Type: COMPLEX / Entity ID: #2, #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: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 112752 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0019772
ELECTRON MICROSCOPYf_angle_d0.35513388
ELECTRON MICROSCOPYf_dihedral_angle_d9.8893496
ELECTRON MICROSCOPYf_chiral_restr0.0331520
ELECTRON MICROSCOPYf_plane_restr0.0031554

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