Nature structural & molecular biology · 2026
Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter.
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Belleza Oliver J V, Zhang Heng, Schmidhammer Helmut, Gonzalez Tye I, Ciotu Cosmin I, Tomašević Nataša, Ocampo Carlo Martin M, Fernando Jomari C, Koehbach Johannes, Schwarz Paula, Al Makhlouf Mounaf, Tajti Gabor, Hasinger Simon, Kastner Nina, Avsar Orcun, Retzl Bernhard, Jäntsch Kathrin, Jiang Yi, Hellinger Roland, Fischer Michael J M, Rosengren K Johan, Gruber Christian W, Villaraza Aaron Joseph L, Stockner Thomas, Spetea Mariana, Xu H Eric, Sitte Harald H
Аннотация
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.