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Papers In Press, published online ahead of print December 12, 2003
Plant Sciences, Tel Aviv University, Tel Aviv 69978
Corresponding Author: mamgur{at}post.tau.ac.il
Scorpion
J. Biol. Chem, 10.1074/jbc.M307531200
Submitted on July 14, 2003
Revised on December 11, 2003
Accepted on December 11, 2003
Dissection of the functional surface of an anti-insect excitatory toxin illuminates a putative hot spot common to all scorpion beta-toxins affecting Na+ channels
-toxins affect the activation of voltage-sensitive sodium channels (NaChs). Although these toxins have been instrumental in the study of channel gating and architecture, little is known about their active site. Using an efficient system for production of recombinant toxins, we analyzed by point mutagenesis the entire surface of the -toxin, Bj-xtrIT, an anti-insect selective excitatory toxin from the scorpion Buthotus judaicus. Each toxin mutant was purified and analyzed using toxicity and binding assays, as well as by circular dichroism spectroscopy to discern between mutations that caused structural changes and those that specifically affected bioactivity. This analysis highlighted a functional discontinuous surface of 1405 Å2 composed of a number of non-polar and three charged amino acids clustered around the main 
-helical motif and the C-tail. Among the charged residues, Glu30 is a center of a putative ‘hot spot’ in the toxin-receptor binding-interface and is shielded from bulk solvent by a hydrophobic ‘gasket’ (Tyr26 and Val34). Comparison of Bj-xtrIT structure with that of other -toxins that are active on mammals, suggests that the ‘hot spot’ and an adjacent non-polar region are spatially conserved. These results highlight for the first time structural elements that constitute a putative ‘pharmacophore’ involved in the interaction of -toxins with receptor site-4 on NaChs. Furthermore, the unique structure of the C-terminal region most likely determines the specificity of excitatory toxins for insect NaChs.
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