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Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity

Joanna Pawlak^*, Stephen P. Mackessy, Nicole M. Sixberry, Enrico A. Stura, Marie Hélène Le Du, Renée Ménez, Chun Shin Foo, André Ménez, Selvanayagam Nirthanan and R. Manjunatha Kini^*,||,1

^* Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore;

School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA;

Département d’Ingénierie et d’Etudes des Protéines, Commissariat à l’Energie Atomique, Gif-sur-Yvette Cedex, France;

Neuropharmacology and Lead Discovery Laboratory, National Neuroscience Institute, Singapore; and

^|| Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA

¹Correspondence: Protein Science Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Science Dr. 4, Singapore 117543. E-mail: dbskinim{at}nus.edu.sg

A novel heterodimeric three-finger neurotoxin, irditoxin, was isolated from venom of the brown treesnake Boiga irregularis (Colubridae). Irditoxin subunit amino acid sequences were determined by Edman degradation and cDNA sequencing. The crystal structure revealed two subunits with a three-finger protein fold, typical for "nonconventional" toxins such as denmotoxin, bucandin, and candoxin. This is the first colubrid three-finger toxin dimer, covalently connected via an interchain disulfide bond. Irditoxin showed taxon-specific lethality toward birds and lizards and was nontoxic toward mice. It produced a potent neuromuscular blockade at the avian neuromuscular junction (IC₅₀=10 nM), comparable to -bungarotoxin, but was three orders of magnitude less effective at the mammalian neuromuscular junction. Covalently linked heterodimeric three-finger toxins found in colubrid venoms constitute a new class of venom peptides, which may be a useful source of new neurobiology probes and therapeutic leads.—Pawlak, J., Mackessy, S. P., Sixberry, N. M., Stura, E. A., Le Du, M. H., Ménez, R., Foo, C. S., Ménez, A., Nirthanan, S., Kini, R. M. Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity.

Key Words: postsynaptic neurotoxin • acetylcholine receptor • neuromuscular junction • snake venom

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