An increasing number of ion channel toxins and related polypeptides have been found
to adopt a common structural motif designated the inhibitor 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
polypeptides. Protein Science 3, 1833-1839). These globular, disulfide-stabilized
molecules come from phylogenetically diverse sources, including spiders, cone shells,
plants and fungi, and have various functions, although many target voltage-gated ion-channels.
The common motif consists of a cystine knot and a triple-stranded, anti-parallel beta-sheet.
Examples of ion-channel toxins known to adopt this structure are the omega-conotoxins
and omega-agatoxins, and, more recently, robustoxin, versutoxin and protein 5 from
spiders, as well as kappa-conotoxin PVIIA and conotoxin GS from cone shells. The variations
on the motif structure exemplified by these structures are described here. We also
consider the sequences of several polypeptides that might adopt this fold, including
SNX-325 from a spider, delta-conotoxin PVIA and the muO-conotoxins from cone shells,
and various plant and fungal polypeptides. The interesting case of the two- and three-disulfide
bridged binding domains of the cellobiohydrolases from the fungus Trichoderma reesei
is also discussed. The compact and robust nature of this motif makes it an excellent
scaffold for the design and engineering of novel polypeptides with enhanced activity
against existing targets, or with activity against novel targets.