Discovery and structure of a potent and highly specific blocker of insect calcium channels.
We have isolated a novel family of insect-selective neurotoxins that appear to be the most potent blockers of insect voltage-gated calcium channels reported to date. These toxins display exceptional phylogenetic specificity, with at least a 10,000-fold preference for insect versus vertebrate calcium channels. The structure of one of the toxins reveals a highly structured, disulfide-rich core and a structurally disordered C-terminal extension that is essential for channel blocking activity. Weak structural/functional homology with omega-agatoxin-IVA/B, the prototypic inhibitor of vertebrate P-type calcium channels, suggests that these two toxin families might share a similar mechanism of action despite their vastly different phylogenetic specificities.
Wang
X H
XH
Department of Biochemistry, University of Connecticut Health Center, Farmington, CT 06032, USA.
Connor
M
M
Wilson
D
D
Wilson
H I
HI
Nicholson
G M
GM
Smith
R
R
Shaw
D
D
Mackay
J P
JP
Alewood
P F
PF
Christie
M J
MJ
King
G F
GF
D000595:Amino Acid Sequence; D000818:Animals; D001516:Bees / Q000166:cytology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D007300:Insect Control / Q000379:methods; D007306:Insecticides / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000235:genetics / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D018408:Patch-Clamp Techniques; D011498:Protein Precursors / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013111:Spider Venoms / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D013112:Spiders; D020867:omega-Agatoxin IVA / Q000737:chemistry
D002121:Calcium Channel Blockers; D007306:Insecticides; D009498:Neurotoxins; D011498:Protein Precursors; D011994:Recombinant Proteins; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; C439676:omega-atracotoxin Hv2a