Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations
Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)<sub>2</sub>(β2)<sub>3</sub> nAChR subunit arrangemen...
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MDPI AG
2020-07-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/18/7/349 |
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| author | Jierong Wen David J. Adams Andrew Hung |
| author_facet | Jierong Wen David J. Adams Andrew Hung |
| author_sort | Jierong Wen |
| collection | DOAJ |
| description | Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)<sub>2</sub>(β2)<sub>3</sub> nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes. |
| first_indexed | 2024-03-10T18:41:31Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T18:41:31Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-6644661d39a746c783e2381d121a02352023-11-20T05:48:12ZengMDPI AGMarine Drugs1660-33972020-07-0118734910.3390/md18070349Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics SimulationsJierong Wen0David J. Adams1Andrew Hung2School of Science, RMIT University, Melbourne, VIC 3000, AustraliaIllawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, AustraliaSchool of Science, RMIT University, Melbourne, VIC 3000, AustraliaNotably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)<sub>2</sub>(β2)<sub>3</sub> nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes.https://www.mdpi.com/1660-3397/18/7/349MD simulationhomology modellingα-conotoxinnicotinic acetylcholine receptor interfaceC-terminal amidation/carboxylation |
| spellingShingle | Jierong Wen David J. Adams Andrew Hung Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations Marine Drugs MD simulation homology modelling α-conotoxin nicotinic acetylcholine receptor interface C-terminal amidation/carboxylation |
| title | Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations |
| title_full | Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations |
| title_fullStr | Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations |
| title_full_unstemmed | Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations |
| title_short | Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations |
| title_sort | interactions of the α3β2 nicotinic acetylcholine receptor interfaces with α conotoxin lsia and its carboxylated c terminus analogue molecular dynamics simulations |
| topic | MD simulation homology modelling α-conotoxin nicotinic acetylcholine receptor interface C-terminal amidation/carboxylation |
| url | https://www.mdpi.com/1660-3397/18/7/349 |
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