Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors
αδ-Bungarotoxins, a novel group of long-chain α-neurotoxins, manifest different affinity to two agonist/competitive antagonist binding sites of muscle-type nicotinic acetylcholine receptors, being more active at the interface of α-δ-subunits. Three isoforms (αδ-BgTx-1-3) were identified in Malayan K...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Portland Press
2019
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| _version_ | 1826258518521413632 |
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| author | Utkin, YN Kuch, U Kasheverov, IE Lebedev, DS Cederlund, E Molles, BE Polyak, I Ivanov, IA Prokopev, NA Ziganshin, RH Jornvall, H Alvelius, G Chanhome, L Warrell, D Mebs, D Bergman, T Tsetlin, VI |
| author_facet | Utkin, YN Kuch, U Kasheverov, IE Lebedev, DS Cederlund, E Molles, BE Polyak, I Ivanov, IA Prokopev, NA Ziganshin, RH Jornvall, H Alvelius, G Chanhome, L Warrell, D Mebs, D Bergman, T Tsetlin, VI |
| author_sort | Utkin, YN |
| collection | OXFORD |
| description | αδ-Bungarotoxins, a novel group of long-chain α-neurotoxins, manifest different affinity to two agonist/competitive antagonist binding sites of muscle-type nicotinic acetylcholine receptors, 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 nicotinic acetylcholine receptors. The toxicity of αδ-BgTx-1 (LD50 0.17-0.28 μg/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 to 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 nicotinic acetylcholine receptors. 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 nicotinic acetylcholine receptors showing up to two orders of magnitude higher affinity for the α-δ site as compared to 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 nicotinic acetylcholine receptors. |
| first_indexed | 2024-03-06T18:35:13Z |
| format | Journal article |
| id | oxford-uuid:0afb38f6-8e76-407b-8a2a-8340f86ab2c8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:35:13Z |
| publishDate | 2019 |
| publisher | Portland Press |
| record_format | dspace |
| spelling | oxford-uuid:0afb38f6-8e76-407b-8a2a-8340f86ab2c82022-03-26T09:27:04ZNovel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0afb38f6-8e76-407b-8a2a-8340f86ab2c8EnglishSymplectic Elements at OxfordPortland Press2019Utkin, YNKuch, UKasheverov, IELebedev, DSCederlund, EMolles, BEPolyak, IIvanov, IAProkopev, NAZiganshin, RHJornvall, HAlvelius, GChanhome, LWarrell, DMebs, DBergman, TTsetlin, VIαδ-Bungarotoxins, a novel group of long-chain α-neurotoxins, manifest different affinity to two agonist/competitive antagonist binding sites of muscle-type nicotinic acetylcholine receptors, 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 nicotinic acetylcholine receptors. The toxicity of αδ-BgTx-1 (LD50 0.17-0.28 μg/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 to 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 nicotinic acetylcholine receptors. 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 nicotinic acetylcholine receptors showing up to two orders of magnitude higher affinity for the α-δ site as compared to 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 nicotinic acetylcholine receptors. |
| spellingShingle | Utkin, YN Kuch, U Kasheverov, IE Lebedev, DS Cederlund, E Molles, BE Polyak, I Ivanov, IA Prokopev, NA Ziganshin, RH Jornvall, H Alvelius, G Chanhome, L Warrell, D Mebs, D Bergman, T Tsetlin, VI Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title | Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title_full | Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title_fullStr | Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title_full_unstemmed | Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title_short | Novel long-chain neurotoxins from Bungarus candidus distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors |
| title_sort | novel long chain neurotoxins from bungarus candidus distinguish the two binding sites in muscle type nicotinic acetylcholine receptors |
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