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 superfamily. 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 structure at 2.45 A resolution suggests that the ion channel binding 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 surface and reduced hydrophobicity.


CONCLUSIONS
Molecular recognition by this Kunitz module appears to diverge considerably from more conventional 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 targeting and explain the remarkable ability of the toxin to avoid binding to non-target membranes. Insight into the mechanism of beta-bungarotoxin gained here may lead to the development of therapeutic strategies against not only pathological cells, but also enveloped viruses.
Kwong
P D
PD
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
McDonald
N Q
NQ
Sigler
P B
PB
Hendrickson
W A
WA
D000595:Amino Acid Sequence; D001665:Binding Sites; D002038:Bungarotoxins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004546:Elapid Venoms / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010640:Phenothiazines / Q000737:chemistry; D010740:Phospholipases / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
C062307:10-N-methylcarbamoyl-3,7-dimethylamino-10H-phenothiazine; D002038:Bungarotoxins; D004546:Elapid Venoms; D010640:Phenothiazines; D015221:Potassium Channels; C005082:notexin; D010740:Phospholipases