101. Discovery and Structure of a Potent and Highly Specific Blocker of Insect Calcium Channels
- Author
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Graham M. Nicholson, Xiu-hong Wang, Mark Connor, Paul F. Alewood, Joel P. Mackay, Ross Smith, Glenn F. King, David Wilson, Harry I. Wilson, Denis C. Shaw, and MacDonald J. Christie
- Subjects
Models, Molecular ,Insecticides ,Biochemistry & Molecular Biology ,Patch-Clamp Techniques ,Molecular Sequence Data ,Neurotoxins ,Spider Venoms ,Biology ,Insect Control ,Biochemistry ,omega-Agatoxin IVA ,medicine ,Animals ,Neurotoxin ,Amino Acid Sequence ,Patch clamp ,Protein Precursors ,Protein precursor ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,Peptide sequence ,Neurons ,Phylogenetic tree ,Voltage-dependent calcium channel ,Calcium channel ,Spiders ,Cell Biology ,Bees ,Calcium Channel Blockers ,Recombinant Proteins ,Mechanism of action ,medicine.symptom - 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.