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- PDB-9pb0: Solution NMR structure of conotoxin AoIA - globular disulfide isomer -

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Basic information

Entry
Database: PDB / ID: 9pb0
TitleSolution NMR structure of conotoxin AoIA - globular disulfide isomer
ComponentsChi-conotoxin-like Ar1311
KeywordsTOXIN / conotoxin / chi-conotoxin / NET-inhibitor
Function / homologytoxin activity / extracellular region / Chi-conotoxin-like Ar1311
Function and homology information
Biological speciesConus araneosus (invertebrata)
MethodSOLUTION NMR / simulated annealing
AuthorsGonzalez, T.I. / Rosengren, K.J.
Funding support Australia, 1items
OrganizationGrant numberCountry
Australian Research Council (ARC) Australia
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
DepositionJun 25, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2026Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Chi-conotoxin-like Ar1311


Theoretical massNumber of molelcules
Total (without water)1,3201
Polymers1,3201
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: NMR Distance Restraints, NOESY data fully consistent with monomer.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 50Molprobity score
RepresentativeModel #1fewest violations

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Components

#1: Protein/peptide Chi-conotoxin-like Ar1311


Mass: 1319.643 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Conus araneosus (invertebrata) / References: UniProt: P0CI23
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-1H TOCSY
121isotropic12D 1H-1H NOESY
131isotropic12D 1H-13C HSQC
141isotropic12D 1H-15N HSQC

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Sample preparation

DetailsType: solution / Contents: 2 mg/mL ArXA-Globular, 90% H2O/10% D2O / Label: A / Solvent system: 90% H2O/10% D2O
SampleConc.: 2 mg/mL / Component: ArXA-Globular / Isotopic labeling: natural abundance
Sample conditionsIonic strength: 0 mM / Label: conditions_1 / pH: 3.5 / PH err: 0.5 / Pressure: ambient / Temperature: 298 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE III HD / Manufacturer: Bruker / Model: AVANCE III HD / Field strength: 700 MHz / Details: equipped with cryoprobe

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Processing

NMR software
NameVersionDeveloperClassification
TopSpin3.7.0Bruker Biospincollection
TopSpin3.7.0Bruker Biospinprocessing
CARA1.9.1Keller and Wuthrichchemical shift assignment
CYANA3.98.15Guntert, Mumenthaler and Wuthrichstructure calculation
CNS1.2Brunger, Adams, Clore, Gros, Nilges and Readrefinement
RefinementMethod: simulated annealing / Software ordinal: 5
Details: Structures were calculated using torsion angle dynamics and refined in explicit solvent using cartesian dynamics.
NMR representativeSelection criteria: fewest violations
NMR ensembleConformer selection criteria: Molprobity score / Conformers calculated total number: 50 / Conformers submitted total number: 20

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