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Mutagenesis of α-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors

1
Biomolecular Sciences Graduate Programs, Boise State University; Boise, ID 83725, USA
2
Department of Chemistry and Biochemistry, Boise State University; Boise, ID 83725, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Toxins 2019, 11(2), 113; https://doi.org/10.3390/toxins11020113
Received: 27 January 2019 / Revised: 10 February 2019 / Accepted: 11 February 2019 / Published: 13 February 2019
(This article belongs to the Special Issue Marine Toxins Affecting Neuronal Function)
Nicotinic acetylcholine receptors (nAChRs) are found throughout the mammalian body and have been studied extensively because of their implication in a myriad of diseases. α-Conotoxins (α-CTxs) are peptide neurotoxins found in the venom of marine snails of genus Conus. α-CTxs are potent and selective antagonists for a variety of nAChR isoforms. Over the past 40 years, α-CTxs have proven to be valuable molecular probes capable of differentiating between closely related nAChR subtypes and have contributed greatly to understanding the physiological role of nAChRs in the mammalian nervous system. Here, we review the amino acid composition and structure of several α-CTxs that selectively target nAChR isoforms and explore strategies and outcomes for introducing mutations in native α-CTxs to direct selectivity and enhance binding affinity for specific nAChRs. This review will focus on structure-activity relationship studies involving native α-CTxs that have been rationally mutated and molecular interactions that underlie binding between ligand and nAChR isoform. View Full-Text
Keywords: α-conotoxins (α-CTxs); nicotinic acetylcholine receptors (nAChRs); mutational analysis; positional scanning synthetic combinatorial libraries (PS-SCL); acetylcholine binding protein (AChBP); protein surface topography (PST); genetic algorithm managed peptide mutant screening (GAMPMS); molecular dynamics (MD); solid phase peptide synthesis (SPPS) α-conotoxins (α-CTxs); nicotinic acetylcholine receptors (nAChRs); mutational analysis; positional scanning synthetic combinatorial libraries (PS-SCL); acetylcholine binding protein (AChBP); protein surface topography (PST); genetic algorithm managed peptide mutant screening (GAMPMS); molecular dynamics (MD); solid phase peptide synthesis (SPPS)
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MDPI and ACS Style

Turner, M.W.; Marquart, L.A.; Phillips, P.D.; McDougal, O.M. Mutagenesis of α-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors. Toxins 2019, 11, 113.

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