9K6X
Structural and functional basis of antinociceptive action of conotoxin AoIA at the noradrenaline transporter
This is a non-PDB format compatible entry.
Summary for 9K6X
| Entry DOI | 10.2210/pdb9k6x/pdb |
| EMDB information | 62139 |
| Descriptor | conotoxin AoIA, Sodium-dependent noradrenaline transporter, [(2~{R})-3-[[(2~{S})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-2-oxidanyl-propyl] (9~{Z},12~{Z})-octadeca-9,12-dienoate, ... (6 entities in total) |
| Functional Keywords | complex, transport protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 150664.22 |
| Authors | Zhang, H.,Harald, S.,Oliver, B.,Xu, E.H. (deposition date: 2024-10-22, release date: 2026-05-06, 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 Cited by 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: 42481720DOI: 10.1038/s41594-026-01838-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.77 Å) |
Structure validation
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