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- Title
Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors.
- Authors
Utkin, Yuri N.; Kuch, Ulrich; Kasheverov, Igor E.; Lebedev, Dmitry S.; Cederlund, Ella; Molles, Brian E.; Polyak, Iakov; Ivanov, Igor A.; Prokopev, Nikita A.; Ziganshin, Rustam H.; Jornvall, Hans; Alvelius, Gunvor; Chanhome, Lawan; Warrell, David A.; Mebs, Dietrich; Bergman, Tomas; Tsetlin, Victor I.
- Abstract
αδ-Bungarotoxins, a novel group of long-chain α-neurotoxins, manifest different affinity to two agonist/competitive antagonist binding sites of muscle-type nicotinic acetylcholinereceptors (nAChRs), being more active at the interface of α-δ subunits. Three isoforms(αδ-BgTx-1-3) were identified in Malayan Krait (Bungarus candidus) from Thailand by genomic DNA analysis; two of them (αδ-BgTx-1 and 2) were isolated from its venom. The toxins comprise 73 amino acid residues and 5 disulfide bridges, being homologous to α-bungarotoxin (α-BgTx), a classical blocker of muscle-type and neuronal α7, α8, and α9α10 nAChRs. The toxicity of αδ-BgTx-1 (LD50 = 0.17-0.28 mg/g mouse, i.p. injection) is essentially as high as that of α-BgTx. In the chick biventer cervicis nerve-muscle preparation, αδ-BgTx-1 completely abolished acetylcholine response, but in contrast with the block by α-BgTx, acetylcholine response was fully reversible by washing. αδ-BgTxs, similar to α-BgTx, bind with high affinity to α7 and muscle-type nAChRs. However, the major difference of αδ-BgTxs from α-BgTx and other naturally occurring α-neurotoxins is that αδ-BgTxs discriminate the two binding sites in the Torpedo californica and mouse muscle nAChRs showing up to two orders of magnitude higher affinity for the α-δ site as compared with α-ε or α-γ binding site interfaces. Molecular modeling and analysis of the literature provided possible explanations for these differences in binding mode; one of the probable reasons being the lower content of positively charged residues in αδ-BgTxs. Thus, αδ-BgTxs are new tools for studies on nAChRs.
- Subjects
THAILAND; CHOLINERGIC receptors; NICOTINIC acetylcholine receptors; BINDING sites; AMINO acid residues; NEUROTOXIC agents; DNA analysis
- Publication
Biochemical Journal, 2019, Vol 476, Issue 8, p1285
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BCJ20180909