The cystine knot structure of ion channel toxins and related polypeptides.
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.
Norton
R S
RS
Biomolecular Research Institute, Parkville, Australia. ray.norton@molsci.csiro.au
Pallaghy
P K
PK
D060848:Agatoxins; D000595:Amino Acid Sequence; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000633:toxicity; D002480:Cellulase / Q000737:chemistry / Q000633:toxicity; D043366:Cellulose 1,4-beta-Cellobiosidase; D020916:Conotoxins; D003545:Cysteine; D003553:Cystine / Q000737:chemistry*; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008974:Mollusca; D008978:Mollusk Venoms / Q000737:chemistry / Q000633:toxicity; D009498:Neurotoxins / Q000737:chemistry* / Q000633:toxicity; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D015202:Protein Engineering; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid; D013111:Spider Venoms / Q000737:chemistry / Q000633:toxicity; D013112:Spiders; D014242:Trichoderma / Q000201:enzymology
D060848:Agatoxins; D002121:Calcium Channel Blockers; D020916:Conotoxins; D007473:Ion Channels; D008978:Mollusk Venoms; D009498:Neurotoxins; D010455:Peptides; D013111:Spider Venoms; C108818:kappa-conotoxin PVIIA; C060465:omega-agatoxin I; D003553:Cystine; D002480:Cellulase; D043366:Cellulose 1,4-beta-Cellobiosidase; D003545:Cysteine