Structural and Functional Elucidation of Peptide Ts11 Shows Evidence of a Novel Subfamily of Scorpion Venom Toxins

Abstract

To date, several families of peptide toxins specifically interacting with ion channels in scorpion venom have been described. One of these families comprise peptide toxins (called KTxs), known to modulate potassium channels. Thus far, 202 KTxs have been reported, belonging to several subfamilies of KTxs (called α, β, γ, κ, δ, and λ-KTxs). Here we report on a previously described orphan toxin from Tityus serrulatus venom, named Ts11. We carried out an in-depth structure-function analysis combining 3D structure elucidation of Ts11 and electrophysiological characterization of the toxin. The Ts11 structure is highlighted by an Inhibitor Cystine Knot (ICK) type scaffold, completely devoid of the classical secondary structure elements (α-helix and/or β-strand). This has, to the best of our knowledge, never been described before for scorpion toxins and therefore represents a novel, 6th type of structural fold for these scorpion peptides. On the basis of their preferred interaction with voltage-gated K channels, as compared to all the other targets tested, it can be postulated that Ts11 is the first member of a new subfamily, designated as ε-KTx.

Dissecting Toxicity: The Venom Gland Transcriptome and the Venom Proteome of the Highly Venomous Scorpion Centruroides limpidus (Karsch, 1879)

“…Scorpion venoms contain toxins that affect these channels (KScTx), as demonstrated with insect and mammalian channels [37]. The KScTx have been classified into seven families (α, β, γ, δ, ε, κ, and λ) depending on their amino acid sequences, length, and 3D-structure [39,40,41]. They have been shown to be active on voltage-gated potassium channels (such as Kv1, Kv3, Kv4, Kv7, Kv11) and calcium-activated potassium channels (KCa1.1 or BK) [37].…”

Drug Discovery on Natural Products: From Ion Channels to nAChRs, from Nature to Libraries, from Analytics to Assays

“…Even if newly discovered bioactive peptides and proteins from venoms may not reach the market as medicines, they still can provide new relevant information for a better understanding of receptor expression and binding site information, and of receptor functions (physiology and structure). In addition, this information can find its way into diagnostics 97,98 and allow for more efficient ways of the recombinant expression of snake venom toxins, such as recombinant viper three-finger toxins studied as potent inhibitors of nAChRs. 99 Furthermore, other applications for these compounds are found, such as in cosmetics 100,101 and pesticides.…”

Scorpion Venom–Toxins that Aid in Drug Development: A Review

“…Voltage-gated sodium channels have enormous contribution in blooming of metastasis as many cancers are enriched with these channels (Hmed et al 2013). It is said that potassium channel has ardent activity in promoting proliferation of tumour cells (Villalonga et al 2007) and SVTs being bona fide blockers of the K + channels can be highly efficacious as active pharmaceutical agents (Petricevich et al 2013;Cremonez et al 2016). This channel seldom acts as therapeutic target in the diagnosis of cardiovascular diseases, autoimmune disorders and inflammation (Bergeron and Bingham 2012).…”