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

Abstract

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 (IC(50)=10 nM), comparable to alpha-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.

Two color morphs of the pelagic yellow-bellied sea snake, Pelamis platura, from different locations of Costa Rica: Snake venomics, toxicity, and neutralization by antivenom

“…Thus, although the results indicated that the major PLA 2 eluted in peak 9 (which accounts for ~20% of the total venom proteins) was not lethal to mice, the possibility that this protein exhibits taxon-specific activity, as reported for other toxins [83][84][85][86][87], requires future detailed investigation. Finally, of relevance from a clinical standpoint, the sea snake antivenom manufactured by CSL in Australia using the venom of E. schistosa displays sufficient immunological cross-reactivity to provide protection from the lethal effects of P.…”

Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)

“…They are most commonly found in the venoms of elapid and hydrophiid snakes. Recently, our laboratory has also demonstrated the presence of 3FTxs from colubrid venoms (12,13), and 3FTx transcripts have been found in the venom gland transcriptome of viperid snakes (14,15). The proteins in this family of toxins share a common structural scaffold of three ␤-sheeted loops emerging from a central core (11,16).…”

“…Muscarinic toxin 1, isolated from the venom of Dendroaspis angusticeps, interacts with mAChR subtype 1 (M1) (29), whereas muscarinic toxin 3 (MT3), isolated from the same snake, interacts with M4 mAChRs (30). In recent years, new 3FTxs with distinct and novel receptor specificities have been characterized and added to this growing library (12,13,(31)(32)(33)(34)(35)(36), justifying their usefulness as pharmacological tools to dissect the cholinergic circuitry to understand the role of individual receptor subtypes or offer clues to the rational design of specific therapeutics.…”

“…(37,38), which is a non-covalently linked homodimer that binds neuronal (␣ 3 ␤ 2 and ␣ 4 ␤ 2 ) but not muscle (␣␤␥␦) nAChRs. More recently, we published the first report of a covalent heterodimeric neurotoxin, irditoxin from the venom of Boiga sp., which was a uniquely irreversible inhibitor of muscle (␣␤␥␦) nAChRs (13). Here, we report the purification, pharmacological characterization, and a high resolution crystal structure of a novel non-covalent homodimeric neurotoxin from the venom of Ophiophagus hannah (King cobra).…”

An investigation of the evolution of the anguimorph lizard venom system

“…Such taxonomic, geographic and ontogenetic variation has been linked to strong natural selection in response to differing prey species (Fry et al, 2003a(Fry et al, ,b,c, 2008Daltry et al, 1996;Sunagar et al, , 2014Brust et al, 2013;Casewell et al, 2013;Gibbs and Mackessy, 2009;Pawlak et al, 2009). …”