STRUCTURE OF BETA(2)-BUNGAROTOXIN - POTASSIUM CHANNEL BINDING BY KUNITZ MODULES AND TARGETED PHOSPHOLIPASE ACTION

Background: beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to a K+ channel binding subunit which is a member of the Kunitz protease inhibitor su perfamily. Toxicity, characterized by blockage of neural transmission, is achieved by the lipolytic action of the phospholipase targeted to the presynaptic membrane by the Kunitz module. Results: The crystal st ructure at 2.45 Angstrom resolution suggests that the ion channel bind ing region of the Kunitz subunit is at the opposite end of the module from the loop typically involved in protease binding. Analysis of the phospholipase subunit reveals a partially occluded substrate-binding s urface and reduced hydrophobicity. Conclusions: Molecular recognition by this Kunitz module appears to diverge considerably from more conven tional superfamily members. The ion channel binding region identified here may mimic the regulatory interaction of endogenous neuropeptides. Adaptations of the phospholipase subunit make it uniquely suited to t argeting and explain the remarkable ability of the toxin to avoid bind ing to non-target membranes. Insight into the mechanism of beta-bungar otoxin gained here may lead to the development of therapeutic strategi es against not only pathological cells, but also enveloped viruses.