STRUCTURE AND FUNCTION OF THE WAGLERINS, PEPTIDE TOXINS FROM THE VENOM OF WAGLER'S PIT VIPER, TROPIDOLAEMUS WAGLERI

The three-fingered α-neurotoxins isolated from the venoms of Elapidae family snakes have long been used as tools for the isolation and characterization of the nicotinic acetylcholine receptor (nAChR). These small proteins cause paralysis and death by binding to the nAChR at the neuromuscular junction and competitively antagonizing the action of acetylcholine. Snakes of the Viperidae family were not previously known to make toxins that target nAChR. A decade ago, four peptides of 22–24 amino acids were characterized from the venom of Wagler's Pit Viper, Tropidolaemus wagleri. These peptides are unique among the lethal components of Viperid venoms in that their lethal effects, like the three-fingered toxins, are mediated by competitive antagonism of muscle nAChR. One of these peptides, called Waglerin-1, also possesses a distinctive selectivity for the α–ε interface binding site of the mouse nAChR, binding with over 2000-fold higher affinity to the α–ε site compared to the α–δ or α–γ binding sites. Furthermore, it binds the α–ε interface site of cloned mouse nAChR with 100-fold higher affinity than both the rat or the human cloned receptors. The amino acid residues of the receptor mediating both the binding site and species selectivity have been determined. Additional work on the structure of the peptide itself has begun to elucidate the residues of the peptide most responsible for its high affinity and selectivity. The peptides produced by this unique snake provide researchers with a new structural template for studying nAChR and other receptors. Additional research into the low molecular weight venom components of T. wagleri and its cousins in the Viperidae family should yield new structural information on receptors and toxins.