Molecular determinants of binding of a wasp toxin (PMTXs) and its analogs in the Na+ channels proteins

The structural specificity of alpha-PMTX, a novel peptide toxin derived fro m wasp venom has been studied on the neuromuscular synapse in the walking l eg of the lobster. alpha-PMTX is known to induce repetitive action potentia ls in the presynaptic axon due to sodium channel inactivation. We synthesiz ed 29 analogs of alpha-PMTX by substituting one or two amino acids and comp ared threshold concentrations of these mutant toxins for inducing repetitiv e action potentials. In 13 amino acid residues of alpha-PMTX, Arg-1, Lys-3 and Lys-12 regulate the toxic activity because substitution of these basic amino acid residues with other amino acid residues greatly changed the pote ncy. Determining the structure-activity relationships of PMTXs will help cl arifying the molecular mechanism of sodium channel inactivation. (C) 2000 E lsevier Science Ireland Ltd. All rights reserved.