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Mar. Drugs 2018, 16(12), 460; https://doi.org/10.3390/md16120460

Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, 117997 Moscow, Russia
2
Department of Neurobiology, Hellenic Pasteur Institute, 127, Vas. Sofias ave., Athens 115 21, Greece
3
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Street 8, bld. 2, 119991 Moscow, Russia
4
PhysBio of MEPhI, Kashirskoye Ave., 31, 115409 Moscow, Russia
Both authors made equal contributions.
*
Author to whom correspondence should be addressed.
Received: 31 October 2018 / Revised: 9 November 2018 / Accepted: 20 November 2018 / Published: 22 November 2018
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Abstract

α-Conotoxins from Conus snails are capable of distinguishing muscle and neuronal nicotinic acetylcholine receptors (nAChRs). α-Conotoxin RgIA and αO-conotoxin GeXIVA, blocking neuronal α9α10 nAChR, are potential analgesics. Typically, α-conotoxins bind to the orthosteric sites for agonists/competitive antagonists, but αO-conotoxin GeXIVA was proposed to attach allosterically, judging by electrophysiological experiments on α9α10 nAChR. We decided to verify this conclusion by radioligand analysis in competition with α-bungarotoxin (αBgt) on the ligand-binding domain of the nAChR α9 subunit (α9 LBD), where, from the X-ray analysis, αBgt binds at the orthosteric site. A competition with αBgt was registered for GeXIVA and RgIA, IC50 values being in the micromolar range. However, high nonspecific binding of conotoxins (detected with their radioiodinated derivatives) to His6-resin attaching α9 LBD did not allow us to accurately measure IC50s. However, IC50s were measured for binding to Aplysia californica AChBP: the RgIA globular isomer, known to be active against α9α10 nAChR, was more efficient than the ribbon one, whereas all three GeXIVA isomers had similar potencies at low µM. Thus, radioligand analysis indicated that both conotoxins can attach to the orthosteric sites in these nAChR models, which should be taken into account in the design of analgesics on the basis of these conotoxins. View Full-Text
Keywords: conotoxins; nicotinic acetylcholine receptors; ligand-binding domain; acetylcholine-binding protein; binding site; radioligand analysis conotoxins; nicotinic acetylcholine receptors; ligand-binding domain; acetylcholine-binding protein; binding site; radioligand analysis
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Kryukova, E.V.; Ivanov, I.A.; Lebedev, D.S.; Spirova, E.N.; Egorova, N.S.; Zouridakis, M.; Kasheverov, I.E.; Tzartos, S.J.; Tsetlin, V.I. Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models. Mar. Drugs 2018, 16, 460.

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