Novel Conotoxins from Conus striatus and Conus kinoshitai Selectively Block TTX-Resistant Sodium Channels
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- 作者：Grzegorz Bulaj ; Peter J. West ; James E. Garrett ; Maren Watkins ; Min-Min Zhang ; Raymond S. Norton ; Brian J. Smith ; Doju Yoshikami ; and Baldomero M. Olivera
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：May 17, 2005
- 年：2005
- 卷：44
- 期：19
- 页码：7259 - 7265
- 全文大小：466K
- 年卷期：v.44,no.19(May 17, 2005)
- ISSN：1520-4995
文摘
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, 
-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 -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 -conotoxins. Our results suggest that the naturally occurringtruncations do not affect the conformation of the C-terminal loops. Taken together, structural and functionaldifferences among -conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionaryengineering" of conotoxin activity.
-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 -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 -conotoxins. Our results suggest that the naturally occurringtruncations do not affect the conformation of the C-terminal loops. Taken together, structural and functionaldifferences among -conotoxins SmIIIA, SIIIA, and KIIIA offer a unique insight into the "evolutionaryengineering" of conotoxin activity.