Evolution has equipped snakes with a potent weapon: venom, honed over millions of years. This lethal secretion serves snakes in both hunting and self-defence, allowing them to immobilize and digest prey as well as deter threats in their environment.
Of the roughly 3000 snake species known, only a minority possess venom, primarily within the Viperidae and Elapidae families. These venomous snakes have become a focal point for research, yielding a wealth of pharmacologically valuable compounds.
Presently, a variety of complementary methodologies are employed to isolate and characterize these peptides from snake venoms. Researchers explore their potential as molecular tools and as inspiration for drug development, employing sophisticated techniques to uncover their applications.
What’s in venom?
Venom represents a potent and diverse concoction, comprising a multitude of molecules including carbohydrates, nucleic acids, amino acids, lipids, proteins, and peptides. Among these, proteins and peptides constitute the predominant components by dry weight and are the primary focus of scientific inquiry and pharmacological exploration.
Snake venoms encompass a spectrum of enzymatic and non-enzymatic proteins and peptides, categorized into various families based on their structural and functional properties. Over time, researchers have identified numerous bioactive proteins and peptides sourced from a wide array of venomous creatures, including snakes, conus snails, scorpions, centipedes, lizards, spiders, sea anemones, bees, and octopuses.
The intriguing appeal of venom peptides
Peptides within snake venom hold a distinct fascination. Despite their inherent toxicity, when appropriately dosed or modified structurally, numerous venom peptides exhibit potential for direct therapeutic applications or serve as promising starting points for drug development.
Three-Finger Toxins
Comprising 60 to 74 amino acid residues, the three-finger toxins constitute a well-known family of polypeptides. Despite their varied functionalities, these peptides share a conserved structure. Characterized by a unique fold, three-finger toxins feature three beta-stranded loops emanating from a hydrophobic globular core. Stabilizing this three-dimensional architecture are four to five disulfide bonds (illustrated in Fig. 1). Their discrete biological functions arise from subtle differences in loop lengths, conformations, and amino acid compositions.
Irditoxin, an innovative toxin exhibiting high taxon-specific neurotoxicity
Irditoxin, a novel heterodimeric three-finger neurotoxin, was discovered within the venom of the brown tree snake Boiga irregularis (Colubridae). Characterized as a nocturnal rear-fanged colubrid, the brown tree snake possesses small, grooved fangs positioned at the rear of its mouth. Though equipped with numerous teeth, venom delivery occurs solely through the last two upper jaw fangs, necessitating wide mouth opening for effective injection. Venom dispersal is facilitated by a chewing motion, employing capillary action along the grooved fangs. Furthermore, the snake often constricts its prey post-venom injection for immobilization during consumption. Predominantly targeting lizards, this snake’s venom primarily aids in prey subjugation, and poses minimal threat to adult humans.
Irditoxin shares only 30% sequence identity with other three-finger toxins, and most of this identity is due to conserved disulfide bridges and structurally important residues. Each subunit possesses four conserved disulfide bridges located in the core region, the reduction of which disturbs the overall conformation and results in total loss of function. The crystal structure of irditoxin revealed a three-finger protein fold, typical for toxins such as denmotoxin, bucandin, and candoxin (see Fig. 1).
All these toxins belong to the and share the same topology, composed of highly conserved beta sheets (see Fig. 2).
Some three-finger toxins act as monomers (for example bucandin and candoxin), while others act as homodimers, or even hetero-dimers.
The kappa-bungarotoxin’s homodimer, for example, is stabilized by intermolecular beta-sheet interactions through finger �3� (see Fig. 3). Irditoxin acts as a heterodimer, having two different subunits (A and B). Each irditoxin subunit possesses an additional cysteine residue, which is involved in inter-subunit disulfide bond between fingers 2A and 1B (see Fig. 3).
The irditoxin heterodimer was the first covalently linked heterodimeric three-finger toxin ever discovered. Thanks to its unique structure, irditoxin is specifically lethal towards birds and lizards, but not toxic toward mice, making it a taxon-specific toxin.
In Conclusion
Snake venoms have long been regarded as a largely unexplored reservoir of distinctive peptides and proteins. These peptides are notably resilient, designed to withstand degradation and neutralization until they reach their intended target within the prey's body.
Nature has ingeniously addressed this challenge by employing highly stable molecular frameworks, predominantly resistant to protease breakdown and capable of evading other immune defences of the prey. Numerous studies have highlighted the significant impact of these venom peptides on essential physiological processes, including blood pressure regulation, homeostasis, and nervous system function.
Peptides not only serve as invaluable molecular probes but also represent promising candidates for drug discovery and design. Their ease of synthesis and reduced potential for eliciting an immune response make them particularly attractive for therapeutic development.
Want to know more about other snake venom toxins? Explore snake venom toxins family in SCOP2.
Deborah Harrus
About the artwork
Grace Arthur (Year 12) from the Stephen Perse Foundation Sixth Form (Cambridge, UK), used a DNA structure picture to display on her laptop, put masking tape on the screen and then traced the picture onto the masking tape, giving it elements of a tree such as roots and leaves. She then selected the structure of irditoxin because she liked the idea that the snake protein could sit on a tree, as well as because this small structure composed only of beta strands, represented as arrows, looked really cool and worked well with the DNA-tree. To add the irditoxin on top of the DNA picture, she flipped the image and traced it onto tracing paper, so that she could easily transfer the picture onto the masking tape. For the final details, she peeled off the masking tape and stuck it onto the paper, carefully aligning each piece correctly.
View the artwork in the virtual .
Structures, proteins and ligands mentioned in this article
Crystal structure of irditoxin PDB ID 2H7Z
Crystal structure of denmotoxin, PDB ID 2H5F
Crystal structure of bucandin, PDB ID 1IJC, PDB ID 1F94
Crystal structure of candoxin, PDB ID 1JGK
Crystal structure of kappa-bungarotoxin, PDB ID 1KBA
Sources
SCOP2 snake venom toxins family
