| Abstract
| - The peptides isolated from venoms of predatory marine Conus snails (“conotoxins”) are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels andreceptors. We report the discovery of two novel TTX-resistant sodium channel blockers, μ-conotoxinsSIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized bycombining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodiumcurrents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frogskeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in theC-terminal region of the two peptides and of the previously characterized μ-conotoxin SmIIIA (whichalso blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their firstN-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residuesin the first loop affects the overall structure of μ-conotoxins. Our results suggest that the naturally occurringtruncations do not affect the conformation of the C-terminal loops. Taken together, structural and functionaldifferences among μ-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the “evolutionaryengineering” of conotoxin activity.
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