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-residue peptide omega-atracotoxin-HV1 (omega-ACTX-HV1) from Hadronyche versuta. We have chemically synthesized and folded omega-ACTX-HV1, shown that it is neurotoxic, ascertained its disulphide bonding pattern, and determined its three-dimensional solution structure using NMR spectroscopy. The structure consists of a solvent-accessible beta-hairpin protruding from a disulphide-bonded globular core comprising four beta-turns. The three intramolecular disulphide bonds from a cystine knot motif similar to that seen in several other neurotoxic peptides. Despite limited sequence identity, omega-ACTX-HV1 displays significant structural homology with the omega-agatoxins and omega-conotoxins, both of which are vertebrate calcium channel antagonists; however, in contrast with these toxins, we show that omega-ACTX-HV1 inhibits insect, but not mammalian, voltage-gated calcium channel currents.
Fletcher
J I
JI
Department of Biochemistry, University of Sydney, New South Wales, Australia.
Smith
R
R
O'Donoghue
S I
SI
Nilges
M
M
Connor
M
M
Howden
M E
ME
Christie
M J
MJ
King
G F
GF
D000595:Amino Acid Sequence; D000818:Animals; D001315:Australia; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D007313:Insecta; D015640:Ion Channel Gating; D009682:Magnetic Resonance Spectroscopy; D008322:Mammals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010526:Periplaneta / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013111:Spider Venoms / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013440:Sulfides; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D009498:Neurotoxins; D013111:Spider Venoms; D013440:Sulfides; C107148:omega-atracotoxin-HV1; D003545:Cysteine