Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Wen, J and Hung, A 2019, 'Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies', Marine Drugs, vol. 17, no. 206, pp. 1-22.


Document type: Journal Article
Collection: Journal Articles

Title Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies
Author(s) Wen, J
Hung, A
Year 2019
Journal name Marine Drugs
Volume number 17
Issue number 206
Start page 1
End page 22
Total pages 22
Publisher M D P I AG
Abstract α-Conotoxins selectively bind to nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets due to their important role in signaling transmission in excitable cells. A previous experimental study has demonstrated that carboxylation of the C-terminal of α-conotoxin LsIA reduces its potency to inhibit human α7 nAChR relative to naturally amidated LsIA. However, little is known about the contribution of conformational changes in the receptor and interactions, induced by C-terminal amidation/carboxylation of conotoxins, to selective binding to nAChRs, since most conotoxins and some disulfide-rich peptides from other conotoxin subfamilies possess a naturally amidated C-terminal. In this study, we employ homology modeling and molecular dynamics (MD) simulations to propose the determinants for differential interactions between amidated and carboxylated LsIAs with α7 nAChR. Our findings indicate an overall increased number of contacts favored by binding of amidated LsIA versus its carboxylated counterpart. Toxinreceptor pairwise interactions, which may play a role in enhancing the potency of the former, include ARG10-TRP77, LEU141 and CYS17-GLN79 via persistent hydrogen bonds and cation-π interactions, which are weakened in the carboxylated form due to a strong intramolecular saltbridge formed by ARG10 and carboxylated C-terminus. The binding of amidated LsIA also induces enhanced movements in loop C and the juxtamembrane Cys-loop that are closely associated with receptor function. Additionally, the impacts of binding of LsIA on the overall structure and intersubunit contacts were examined using inter-residue network analysis, suggesting a clockwise tilting of the α7 C and F loops upon binding to carboxylated LsIA, which is absent for amidated LsIA binding. The predicted molecular mechanism of LsIA binding to the α7 receptor may provide new insights into the important role of the C-terminal in the binding potency of conotoxins at neuronal nAChRs for pharmacol
Subject Biomolecular Modelling and Design
Keyword(s) homology modeling
MD simulation
α-conotoxin
nicotinic acetylcholine receptor
C-terminal amidation/carboxylation
DOI - identifier 10.3390/md17040206
Copyright notice © 2019 by the authors. Licensee MDPI, Basel, Switzerland
ISSN 1660-3397
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