THE STRUCTURE OF A NOVEL INSECTICIDAL NEUROTOXIN, OMEGA-ATRACOTOXIN-HV1, FROM THE VENOM OF AN AUSTRALIAN FUNNEL-WEB SPIDER

A family of potent insecticidal toxins has recently been isolated from the venom of Australian funnel web spiders. Among these is the 37-res idue peptide omega-atracotoxin-HV1 (omega-ACTX-HV1) from Hadronyche ve rsuta. We have chemically synthesized and folded omega-ACTX-HV1, shown that it is neurotoxic, ascertained its disulphide bonding pattern, an d determined its three-dimensional solution structure using NMR spectr oscopy. The structure consists of a solvent-accessible beta-hairpin pr otruding from a disulphide-bonded globular core comprising four beta-t urns. The three intramolecular disulphide bonds form a cystine knot mo tif similar to that seen in several other neurotoxic peptides. Despite limited sequence identity, omega-ACTX-HV1 displays significant struct ural homology with the omega-agatoxins and omega-conotoxins, both of w hich are vertebrate calcium channel antagonists; however, in contrast with these toxins, we show that omega-ACTX-HV1 inhibits insect, but no t mammalian, voltage-gated calcium channel currents.