title: Discovery and structure of a potent and highly specific blocker of insect calcium channels.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: X H
authors.initials: XH
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Connor
authors.forename: D
authors.initials: D
authors.lastname: Wilson
authors.forename: H I
authors.initials: HI
authors.lastname: Wilson
authors.forename: G M
authors.initials: GM
authors.lastname: Nicholson
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Shaw
authors.forename: J P
authors.initials: JP
authors.lastname: Mackay
authors.forename: P F
authors.initials: PF
authors.lastname: Alewood
authors.forename: M J
authors.initials: MJ
authors.lastname: Christie
authors.forename: G F
authors.initials: GF
authors.lastname: King
mesh_terms: 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
chemical_list: 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