Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels

Bulaj, G; West, PJ; Garrett, JE; Marsh, M; Zhang, MM; Norton, RS; Smith, BJ; Yoshikami, D; Olivera, BM

Author(s): Bulaj, G; West, PJ; Garrett, JE; Marsh, M; Zhang, MM; Norton, RS; Smith, BJ; Yoshikami, D; Olivera, BM;
Details: Publication Year 2005-05-17,Volume 44,Issue #19,Page 7259-7265
Journal Title: BIOCHEMISTRY
Publication Type: Journal Article
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 and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, μ-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were identified and characterized by combining molecular techniques and chemical synthesis. Both peptides inhibit TTX-resistant sodium currents in neurons of frog sympathetic and dorsal root ganglia but poorly block action potentials in frog skeletal muscle, which are mediated by TTX-sensitive sodium channels. The amino acid sequences in the C-terminal region of the two peptides and of the previously characterized μ-conotoxin SmIIIA (which also blocks TTX-resistant channels) are similar, but the three peptides differ in the length of their first N-terminal loop. We used molecular dynamics simulations to analyze how altering the number of residues in the first loop affects the overall structure of μ-conotoxins. Our results suggest that the naturally occurring truncations do not affect the conformation of the C-terminal loops. Taken together, structural and functional differences among μ-conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionary engineering" of conotoxin activity.
Publisher: AMER CHEMICAL SOC
Keywords: MU-CONOTOXIN; MOLECULAR-MECHANISMS; SYMPATHETIC-GANGLIA; NEURONS; PIIIA; INHIBITOR; DYNAMICS; SUBTYPES; CURRENTS; PEPTIDE
Publisher's Version: https://doi.org/10.1021/bi0473408
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2005-05-17 12:00:00