DETERMINATION OF THE 3-DIMENSIONAL SOLUTION STRUCTURE OF NOXIUSTOXIN - ANALYSIS OF STRUCTURAL DIFFERENCES WITH RELATED SHORT-CHAIN SCORPIONTOXINS

The 3D structure of noxiustoxin, the first identified scorpion toxin a cting on K+ channels, has been elucidated by NMR and molecular modelin g. Thirty-nine solution structures were calculated using 572 distance and 42 dihedral restraints. The average atomic rms deviation between t he refined structures and the mean structure is 0.75 Angstrom for the backbone atoms. Noxiustoxin adopts a alpha/beta scaffold constituted o f 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 be tween the 3D structure of noxiustoxin and those of other structurally and functionally related scorpion toxins (charybdotoxin, POS-NH2 kalio toxin) revealed a bending capacity of the helix and a variability in t he relative orientations between the helix and the beta-sheet. These t wo features highlight the plasticity of the alpha/beta scaffold and of fer a structural explanation for the capacity of the fold to accommoda te an additional alanine residue in the Gly-x-Cys pattern of a previou sly proposed consensus sequence [Bontems et al. (1991) Science 254, 15 21-1523]. Our structural data also emphasize the possibility that the beta-sheet of NTX is implicated in the capacity of NTX to recognize vo ltage-dependent K+ channels.