Structure, Function, and Chemical Synthesis of Vaejovis mexicanus Peptide 24: A Novel Potent Blocker of Kv1.3 Potassium Channels of Human T Lymphocytes

Abstract

Animal venoms are rich sources of ligands for studying ion channels and other pharmacological targets. Proteomic analyses of the soluble venom from the Mexican scorpion Vaejovis mexicanus smithi showed that it contains more than 200 different components. Among them, a 36-residue peptide with a molecular mass of 3864 Da (named Vm24) was shown to be a potent blocker of Kv1.3 of human lymphocytes (K(d) ∼ 3 pM). The three-dimensional solution structure of Vm24 was determined by nuclear magnetic resonance, showing the peptide folds into a distorted cystine-stabilized α/β motif consisting of a single-turn α-helix and a three-stranded antiparallel β-sheet, stabilized by four disulfide bridges. The disulfide pairs are formed between Cys6 and Cys26, Cys12 and Cys31, Cys16 and Cys33, and Cys21 and Cys36. Sequence analyses identified Vm24 as the first example of a new subfamily of α-type K(+) channel blockers (systematic number α-KTx 23.1). Comparison with other Kv1.3 blockers isolated from scorpions suggests a number of structural features that could explain the remarkable affinity and specificity of Vm24 toward Kv1.3 channels of lymphocytes.

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

“…The a-KTx is the best studied family; its members are small basic peptides (up to 4 kDa) consisting of 23 to 40 amino acids with the structure stabilized by three to four disulfide bridges. To date, the a-KTx family is classified into 27 subfamilies (http://www.uniprot.org/docs/scorpktx) Goudet et al, 2002;Huys et al, 2004;Rodríguez de la Vega and Possani, 2004;Tan et al, 2006;Zhijian et al, 2006;Gurrola et al, 2012) with K 1 channel affinities varying in the micromolar to picomolar range. The a-KTx toxins target mainly the voltage-gated potassium (K v ) channels, especially the K v 1 family members and some Ca 21 -activated K 1 channels ; Rodríguez de la Vega and .…”

Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant

“…This 36-mer peptide consists of α-helix and β-strands, stabilized by four pairs of disulfide bonds (35). It has a K d ∼3 pM for Kv1.3 and >1,500-fold selectivity over Kv1.1, Kv1.2, KCa1.1, and KCa3.1 (36).…”

“…Moka1 and Vm24 toxin peptides were synthesized in solid phase by InnoPep. Peptide folding, HPLC purification, and LC-MS validation were performed based on previously published procedures (28,35).…”

Scorpion toxin peptide action at the ion channel subunit level

“…Inhibit current, ShIR, Xenopus oocytes, 1 mM, (Cerni et al, 2014) Inhibit current, Rat, Xenopus oocytes, 1 mM, (Cerni et al, 2014) Inhibit current, CL1023, Kd ¼ 0.21 nM, (Werkman et al, 1993); Inhibit current, Rat, Xenopus oocytes, 1 mM, (Cerni et al, 2014) Inhibit current, Mouse, Xenopus oocytes, Kd ¼ 3.9 nM, (Rodrigues et al, 2003); Inhibit current, Mouse, L929, Kd ¼ 198 nM, (Rodrigues et al, 2003); Inhibit current, Rat, Xenopus oocytes, 1 mM, (Cerni et al, 2014) Inhibit current, Rat, Xenopus oocytes, 1 mM, (Cerni et al, 2014) Tst26 a-KTx 4.6 Tityus stigmurus Inhibit current, Human, COS7, Kd ¼ 1.9 nM, (Papp et al, 2009) Inhibit current, Human T lymphocyte, Kd ¼ 10.7 nM, (Papp et al, 2009) (Varga et al, 2012) Inhibit current, Human, COS7, Kd ¼ 5e10 nM, (Varga et al, 2012) Inhibit current, Human T lymphocytes, Kd ¼ 3 pM, (Gurrola et al, 2012); Inhibit current, Human T lymphocytes, Kd ¼ 2.9 pM, (Varga et al, 2012) a-KTx 2.14…”