Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
Toxicon
; 53(1): 90-8, 2009 Jan.
Article
em En
| MEDLINE
| ID: mdl-18950653
ABSTRACT
Described herein is a general approach to identify novel compounds using the biodiversity of a megadiverse group of animals; specifically, the phylogenetic lineage of the venomous gastropods that belong to the genus Conus ("cone snails"). Cone snail biodiversity was exploited to identify three new mu-conotoxins, BuIIIA, BuIIIB and BuIIIC, encoded by the fish-hunting species Conus bullatus. BuIIIA, BuIIIB and BuIIIC are strikingly divergent in their amino acid composition compared to previous mu-conotoxins known to target the voltage-gated Na channel skeletal muscle subtype Na(v)1.4. Our preliminary results indicate that BuIIIB and BuIIIC are potent inhibitors of Na(v)1.4 (average block approximately 96%, at a 1muM concentration of peptide), displaying a very slow off-rate not seen in previously characterized mu-conotoxins that block Na(v)1.4. In addition, the three new C. bullatus mu-conopeptides help to define a new branch of the M-superfamily of conotoxins, namely M-5. The exogene strategy used to discover these Na channel-inhibiting peptides was based on both understanding the phylogeny of Conus, as well as the molecular genetics of venom mu-conotoxin peptides previously shown to generally target voltage-gated Na channels. The discovery of BuIIIA, BuIIIB and BuIIIC Na channel blockers expands the diversity of ligands useful in determining the structure-activity relationship of voltage-gated sodium channels.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Conotoxinas
/
Bloqueadores dos Canais de Sódio
/
Biodiversidade
/
Caramujo Conus
Limite:
Animals
Idioma:
En
Revista:
Toxicon
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos