α4/3 Conotoxins: phylogenetic distribution, functional properties, and structure–function insights

This review examines the α4/3 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 α‐ImI, the founding α4/3 toxin, and two other α4/3 toxins, α‐ImII and α‐RgIA. These three toxins all inhibit nicotinic acetylcholine receptors (nAChRs) belonging to a subset of nAChRs that are composed of only α subunits; they are, however, diverse in terms of the all‐α subtype they preferentially antagonize and the receptor site that they bind to. We thus speculate that the α4/3 toxins may be a rich source of functionally diverse all‐α subunit nAChR inhibitors. We review extensive work that has established a detailed model for α‐ImI binding to one of its preferred nAChR subtypes (the α7 nAChR) and, by comparing the α‐ImI, α‐ImII and α‐RgIA sequences demonstrate how structural features of α4/3 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 α4/3 peptides. We also speculate on how rational modification of α4/3 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. © 2007 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 7: 341–353; 2007: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20131