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J. Biol. Chem., Vol. 281, Issue 39, 29030-29041, September 29, 2006

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Denmotoxin, a Three-finger Toxin from the Colubrid Snake Boiga dendrophila (Mangrove Catsnake) with Bird-specific Activity^*

Joanna Pawlak, Stephen P. Mackessy, Bryan G. Fry¹, Madhav Bhatia^¶, Gilles Mourier^||, Carole Fruchart-Gaillard^||, Denis Servent^||, Renée Ménez^||, Enrico Stura^||, André Ménez^||, and R. Manjunatha Kini^**2

From the Department of Biological Sciences, Faculty of Science, and the ^¶Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore 117543, the School of Biological Sciences, University of Northern Colorado, Greeley, Colorado 80639-0017, the ^||Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'Energie Atomique, Gif-sur-Yvette Cedex 91191, France, and the ^**Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Boiga dendrophila (mangrove catsnake) is a colubrid snake that lives in Southeast Asian lowland rainforests and mangrove swamps and that preys primarily on birds. We have isolated, purified, and sequenced a novel toxin from its venom, which we named denmotoxin. It is a monomeric polypeptide of 77 amino acid residues with five disulfide bridges. In organ bath experiments, it displayed potent postsynaptic neuromuscular activity and irreversibly inhibited indirectly stimulated twitches in chick biventer cervicis nerve-muscle preparations. In contrast, it induced much smaller and readily reversible inhibition of electrically induced twitches in mouse hemidiaphragm nerve-muscle preparations. More precisely, the chick muscle ₁-nicotinic acetylcholine receptor was 100-fold more susceptible compared with the mouse receptor. These data indicate that denmotoxin has a bird-specific postsynaptic activity. We chemically synthesized denmotoxin, crystallized it, and solved its crystal structure at 1.9 Å by the molecular replacement method. The toxin structure adopts a non-conventional three-finger fold with an additional (fifth) disulfide bond in the first loop and seven additional residues at its N terminus, which is blocked by a pyroglutamic acid residue. This is the first crystal structure of a three-finger toxin from colubrid snake venom and the first fully characterized bird-specific toxin. Denmotoxin illustrates the relationship between toxin specificity and the primary prey type that constitutes the snake's diet.

Received for publication, June 19, 2006 , and in revised form, July 21, 2006.

The atomic coordinates and structure factors (code 2H5F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) DQ366293 [GenBank] .

^* This work was supported by a Biomedical Research Council grant from the Agency for Science, Technology and Research, Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Australian Venom Research Unit, School of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia.

² To whom correspondence should be addressed: Protein Science Lab., Dept. of Biological Sciences, Faculty of Science, National University of Singapore, Science Dr. 4, Singapore 117543. Tel.: 65-6516-5235; Fax: 65-6779-2486; E-mail: dbskinim{at}nus.edu.sg.

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