α4/3 conotoxins:: Phylogenetic distribution, functional properties, and structure-function insights

This review examines the alpha 4/3 conotoxins as an example of molecular diversity in a class of compounds that have evolved in a group of closely related species in a single phylogenetic lineage. The species examined belong to Stephanoconus, a clade of Conus, a genus that contains 500-700 different species of carnivorous marine snails. We examine earlier work that describes the identification and characterization of alpha-ImI, the founding alpha 4/3 toxin, and two other (alpha 4/3 toxins, alpha-ImII and alpha-RgIA. These three toxins all inhibit nicotinic acetylcholine receptors (nAChRs) belonging to a subset of nAChRs that are composed of only alpha subunits; they are, however, diverse in terms of the all-a subtype they preferentially antagonize and the receptor site that they bind to. We thus speculate that the alpha 4/3 toxins may be a rich source of functionally diverse all-alpha subunit nAChR inhibitors. We review extensive work that has established a detailed model for alpha-ImI binding to one of its preferred nAChR subtypes (the alpha 7 nAChR) and, by comparing the alpha-ImI, alpha-ImII and alpha-RgIA sequences demonstrate how structural features of alpha 4/3 peptides that account for their diverse functional properties can be identified. This approach is extended to derive models of receptor-toxin binding that may account for the different subtype specificities of alpha 4/3 peptides. We also speculate on how rational modification of alpha 4/3 toxins may allow engineering of ligands with desired subtype specificities. The chemical diversity produced by the closely related animals in Stephanoconus is thus functionally differentiated, although structurally homologous. (C) 2007 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.