CONFORMATIONAL-ANALYSIS OF A TOXIC PEPTIDE FROM TRIMERESURUS-WAGLERI WHICH BLOCKS THE NICOTINIC ACETYLCHOLINE-RECEPTOR

The 22-residue toxic peptide (WTX1) from the venom of the Southeast As ian snake Trimeresurus wagleri has multiple sites of action, but its l ethal effect has been attributed to blocking the postsynaptic acetylch oline receptor at the neuromuscular junction. The 3-dimensional struct ure of WTX1 was studied using 2-dimensional nuclear magnetic resonance spectroscopy, circular dichroism, and computer simulations, In aqueou s solution, WTX1 was shown to have extended and flexible ''tails'' def ined by a short, rigid disulfide-bonded loop. The flexible regions can undergo structural rearrangement when moved from an aqueous to a less polar environment and may contribute to its effectiveness at differen t receptor sites, By substituting Gly or Phe for His at position 10, s ignificant effects on the disulfide bond formation and, thereby, the a ctivity of the peptide were observed, These results suggest that even subtle differences in single residues can have profound effects on the dynamics of folding, disulfide bond formation, and activity of this t oxic peptide.