Determination of the three-dimensional solution structure of noxiustoxin: Analysis of structural differences with related short-chain scorpion toxins

The 3D structure of noxiustoxin, the first identified scorpion toxin acting on K+ channels, has been elucidated by NMR and molecular modeling. Thirty-nine solution structures were calculated using 572 distance and 42 dihedral restraints. The average atomic rms deviation between the refined structures and the mean structure is 0.75 Angstrom for the backbone atoms. Noxiustoxin adopts a alpha/beta scaffold constituted of a three-stranded beta-sheet (residues 2-3, 25-30, 33-38) linked to a helix (residues 10-20) through two disulfide bridges. A comparison between the 3D structure of noxiustoxin and those of other structurally and functionally related scorpion toxins (charybdotoxin, POS-NH2 kaliotoxin) revealed a bending capacity of the helix and a variability in the relative orientations between the helix and the beta-sheet. These two features highlight the plasticity of the alpha/beta scaffold and offer a structural explanation for the capacity of the fold to accommodate an additional alanine residue in the Gly-x-Cys pattern of a previously proposed consensus sequence [Bontems et al. (1991) Science 254, 1521-1523]. Our structural data also emphasize the possibility that the beta-sheet of NTX is implicated in the capacity of NTX to recognize voltage-dependent K+ channels.