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Article

Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations

1
School of Science, RMIT University, Melbourne, VIC 3000, Australia
2
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2020, 18(7), 349; https://doi.org/10.3390/md18070349
Received: 30 May 2020 / Revised: 27 June 2020 / Accepted: 30 June 2020 / Published: 3 July 2020
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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)2(β2)3 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. View Full-Text
Keywords: MD simulation; homology modelling; α-conotoxin; nicotinic acetylcholine receptor interface; C-terminal amidation/carboxylation MD simulation; homology modelling; α-conotoxin; nicotinic acetylcholine receptor interface; C-terminal amidation/carboxylation
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MDPI and ACS Style

Wen, J.; Adams, D.J.; Hung, A. Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations. Mar. Drugs 2020, 18, 349. https://doi.org/10.3390/md18070349

AMA Style

Wen J, Adams DJ, Hung A. Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations. Marine Drugs. 2020; 18(7):349. https://doi.org/10.3390/md18070349

Chicago/Turabian Style

Wen, Jierong, David J. Adams, and Andrew Hung. 2020. "Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations" Marine Drugs 18, no. 7: 349. https://doi.org/10.3390/md18070349

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