Pd. Kwong et al., STRUCTURE OF BETA(2)-BUNGAROTOXIN - POTASSIUM CHANNEL BINDING BY KUNITZ MODULES AND TARGETED PHOSPHOLIPASE ACTION, Structure, 3(10), 1995, pp. 1109-1119
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.