This entry consists of the huwentoxin-II (HWTX-II) family of toxins secreted by spiders. These toxins are found in venom that secreted from the bird spider Selenocosmia huwena Wang. The HWTX-II adopts a novel scaffold different from the ICK motif that is found in other huwentoxins. HWTX-II consists of 37 amino acids residues including six cysteines involved in three disulphide bridges [].
Spiders are widely acknowledged to produce potent and selective toxins. In addition to the conventional neurotoxins and cytotoxins, venom of lynx spiders (genus Oxyopes) was found to contain two-domain modular toxins named spiderines: OspTx1a, 1b, 2a and 2b [, , ]. Spiderines consist of two distinct modules separated by a short linker. The N-terminal part (~40 residues) contains no cysteine residues, is highly cationic, forms amphipathic alpha- helical structures in a membrane-mimicking environment, and shows potent cytolytic effects on cells of various origins. The short linker resembles closely the processing quadruplet motif (PQM), which is known to indicate the processing cleavage site in precursors of spider toxins and separate the prosequence from the mature chain. The C-terminal part (~60 residues) is a disulfide rich domain reticulated by five S-S bridges that is homologous to one-domain oxytoxins (OxyTx1 and OxyTx2) from Oxypes species. Oxytoxins are disulphide-rich polypeptides that contain five disulfide bridges and block L-, N- and P/Q-type voltage-sensitive calcium ion channels (VSCCs) []. The core of the oxytoxin-like domain is the inhibitor cystine knot (ICK) or knottin motif. The domain is stabilised by five disulfides and 13 hydrogen bonds. Two antiparallel β-strands form a short β-sheet, and there are two β-turns in the N-terminal part of of the domain. C1-C5, C2-C6, and C4-C9 disulfides contribute to the ICK motif, whereas C7-C8 stabilises the extended loop of the β-hairpin and C3-C10 staples the lengthy C-terminal of the domain to its core [].This entry represents the oxytoxin-type ICK domain.
This family members are 56-59 residue mu-diguetoxin-1 and beta-diguetoxin-1 toxins, which have been isolated from the weaving spider, Diguetia canities. These toxins were isolated as a result of their potent insect paralytic activities, and designated beta-DGTX-Dc1a, mu-DGTX-Dc1b and mu-DGTX-Dc1c (formerly DTX9.2, DTX11 and DTX12) []. Diguetoxin-Dc1a (Dc1a) has been structurally characterised and shown to have disulfide bonds which form a classical inhibitor cysteine knot (ICK) motif in which the Cys13-Cys26 and Cys20-Cys40 disulfide bonds and the intervening sections of the polypeptide backbone form a 23-residue ring that is pierced by the Cys25-Cys54 disulfide bond. This ICK motif is commonly found in spider toxins, and this particular scaffold provides these peptides (so-called knottins) with an unusually high degree of chemical, thermal and biological stability. Dc1a contains an additional disulfide bond (Cys42-Cys52) that appears to serve as a molecular staple which limits the flexibility of a disordered serine-rich hairpin loop. The extended N terminus of Dc1a along with an unusually large loop between Cys26 and Cys40 enables the formation of an N-terminal three-stranded antiparallel β-sheet that is not found in any other knottin. The molecular surface of Dc1a contains a relatively uniform distribution of charged residues; moreover, there are no distinct clusters of hydrophobic residues that might mediate an interaction with lipid bilayers [].
