Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i>
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integratio...
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| Format: | Article |
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MDPI AG
2019-09-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/17/9/535 |
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| author | Steve Peigneur Prabha Devi Andrea Seldeslachts Samuthirapandian Ravichandran Loïc Quinton Jan Tytgat |
| author_facet | Steve Peigneur Prabha Devi Andrea Seldeslachts Samuthirapandian Ravichandran Loïc Quinton Jan Tytgat |
| author_sort | Steve Peigneur |
| collection | DOAJ |
| description | The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of <i>Conus milneedwardsi.</i> The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in <i>Xenopus laevis</i> oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types. |
| first_indexed | 2024-04-12T19:49:49Z |
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| id | doaj.art-5b5633fb749f47fba7e3cbc7e43c35f2 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-12T19:49:49Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-5b5633fb749f47fba7e3cbc7e43c35f22022-12-22T03:18:51ZengMDPI AGMarine Drugs1660-33972019-09-0117953510.3390/md17090535md17090535Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i>Steve Peigneur0Prabha Devi1Andrea Seldeslachts2Samuthirapandian Ravichandran3Loïc Quinton4Jan Tytgat5Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumToxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumToxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumCenter of Advanced Study in Marine Biology, Annamalai University, Parangipettai, Tamil Nadu 608 502, IndiaLaboratory of Mass Spectrometry, Department of Chemistry, University of Liège, 4000 Liège, BelgiumToxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumThe a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of <i>Conus milneedwardsi.</i> The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in <i>Xenopus laevis</i> oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types.https://www.mdpi.com/1660-3397/17/9/535cone snail toxinsconopeptideα-conotoxindrug developmentelectrophysiologyion channel diseasesnicotinic acetylcholine receptor |
| spellingShingle | Steve Peigneur Prabha Devi Andrea Seldeslachts Samuthirapandian Ravichandran Loïc Quinton Jan Tytgat Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> Marine Drugs cone snail toxins conopeptide α-conotoxin drug development electrophysiology ion channel diseases nicotinic acetylcholine receptor |
| title | Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> |
| title_full | Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> |
| title_fullStr | Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> |
| title_full_unstemmed | Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> |
| title_short | Structure-Function Elucidation of a New α-Conotoxin, MilIA, from <i>Conus milneedwardsi</i> |
| title_sort | structure function elucidation of a new α conotoxin milia from i conus milneedwardsi i |
| topic | cone snail toxins conopeptide α-conotoxin drug development electrophysiology ion channel diseases nicotinic acetylcholine receptor |
| url | https://www.mdpi.com/1660-3397/17/9/535 |
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