THE CYSTINE KNOT STRUCTURE OF ION-CHANNEL TOXINS AND RELATED POLYPEPTIDES

An increasing number of ion channel toxins and related polypeptides ha ve been found to adopt a common structural motif designated the inhibi tor cystine knot motif (Pallaghy P. K., Nielsen, K. J., Craik, D. J., Norton, R. S. (1994) A common structural motif incorporating a cystine knot and triple-stranded beta-sheet in toxic and inhibitory polypepti des. Protein Science 3, 1833-1839). These globular, disulfide-stabiliz ed molecules come from phylogenetically diverse sources, including spi ders, cone shells, plants and fungi, and have various functions, altho ugh many target voltage-gated ion-channels. The common motif consists of a cystine knot and a triple-stranded, anti-parallel beta-sheet. Exa mples of ion-channel toxins known to adopt this structure are the omeg a-conotoxins and omega-agatoxins, and, more recently, robustoxin, vers u-toxin and protein 5 from spiders, as well as kappa-conotoxin PVIIA a nd conotoxin GS from cone shells. The variations on the motif structur e exemplified by these structures are described here. We also consider the sequences of several polypeptides that might adopt this fold, inc luding SNX-325 from a spider, delta-conotoxin PVIA and the mu O-conoto xins from cone shells, and various plant and fungal polypeptides. The interesting case of the two- and three-disulfide bridged binding domai ns of the cellobiohydrolases from the fungus Trichoderma reesei is als o discussed. The compact and robust nature of this motif makes it an e xcellent scaffold for the design and engineering of novel polypeptides with enhanced activity against existing targets, or with activity aga inst novel targets. (C) 1998 Elsevier Science Ltd. All rights reserved .