Delta-atracotoxins (ACTXs) are peptide toxins isolated from the venom of Australian funnel-web spiders that inhibit conversion of the sodium channel from the open to the inactivated state, resulting in sodium current remaining at membrane potentials where inactivation is normally complete. They induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a selective slowing of tetrodotoxin (TTX) voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 [1,2].

All delta-ACTXs are highly homologous 42-residue peptides with no significant sequence homology with any presently known neurotoxins. The toxins have a high proportion of basic residues and are cross-linked by four conserved intramolecular disulfide bonds. Delta-ACTXs comprise a core β region containing a triple-stranded antiparallel β-sheet and a thumb-like extension protruding from the β region (see <PDB:VTX>) [1,2]. The β region of delta-ACTXs contains a 'disulfide-knot', which places them in a class of toxins and inhibitory polypeptides with 'an inhibitor cystine-knot' (ICK) motif [3].

The delta-ACTX family includes:

• Delta-ACTX-Ar1 (Robustoxin) from Atrax robustus (Funnel-web spider),
• Delta-ACTX-Hv1 (versutoxin) and Delta-ACTX-Hv1b from Hadronyche versuta Blue mountains funnel-web spider) (Atrax versutus).
• Neurotoxin Magi 4 from Macrothele gigas (Spider),
• Delta-missulenatoxin-Mb1a from Missulena bradleyi (Eastern mouse spider),

Delta-ACTX family proteins have a [C-C-CCC-C-C-C] cysteine arrangement. The three dimensional structure of delta-ACTXs possesses a knottin scaffold (see <PDOC60004>) [E1] with a fourth pair (I-IV) of cysteine residues (marked '#' in the following schematic representation) involved in an additional disulfide linkage. The cystine-knot motif in delta-ACTXs provides high stability and maintains the tertiary structure.

                              +----------------+
                              | +--------------|-----------+
                 #            |#|              |           |
                 CxxxxxxCxxxxxCCCxxxCxxxxxxxxxxCxxxxxxxxxxxC
                 |      |      |    |
                 +------|------+    |
                        +-----------+

'C': conserved cysteine involved in disulfide bond
'#': fourth pair of the cysteine residue

Our signature pattern for delta-ACTXs contains the eight conserved cysteines involved in disulfide bonds.