9PB0

Solution NMR structure of conotoxin AoIA - globular disulfide isomer

Summary for 9PB0

• Entry DOI: 10.2210/pdb9pb0/pdb
• NMR Information: BMRB: 31256
• Descriptor: Chi-conotoxin-like Ar1311 (1 entity in total)
• Functional Keywords: conotoxin, chi-conotoxin, net-inhibitor, toxin
• Biological source: Conus araneosus
• Total number of polymer chains: 1
• Total formula weight: 1319.64

Authors

Gonzalez, T.I.,Rosengren, K.J. (deposition date: 2025-06-25, release date: 2026-07-29, Last modification date: 2026-08-05)

Primary citation

Belleza, O.J.V.,Zhang, H.,Schmidhammer, H.,Gonzalez, T.I.,Ciotu, C.I.,Tomasevic, N.,Ocampo, C.M.M.,Fernando, J.C.,Koehbach, J.,Schwarz, P.,Al Makhlouf, M.,Tajti, G.,Hasinger, S.,Kastner, N.,Avsar, O.,Retzl, B.,Jantsch, K.,Jiang, Y.,Hellinger, R.,Fischer, M.J.M.,Rosengren, K.J.,Gruber, C.W.,Villaraza, A.J.L.,Stockner, T.,Spetea, M.,Xu, H.E.,Sitte, H.H.
Structural and functional basis of antinociceptive action of chi-conotoxin AoIA at the noradrenaline transporter.
Nat.Struct.Mol.Biol., 2026

PubMed 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 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.

PubMed: 42481720
DOI: 10.1038/s41594-026-01838-z

Experimental method

SOLUTION NMR