Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Egyetem ter. 1, 4032 Debrecen, Hungary.
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Av. Universidad 2001, Cuernavaca 62210, Mexico.
Toxins (Basel). 2023 Aug 15;15(8):506. doi: 10.3390/toxins15080506.
Seven new peptides denominated CboK1 to CboK7 were isolated from the venom of the Mexican scorpion and their primary structures were determined. The molecular weights ranged between 3760.4 Da and 4357.9 Da, containing 32 to 39 amino acid residues with three putative disulfide bridges. The comparison of amino acid sequences with known potassium scorpion toxins (KTx) and phylogenetic analysis revealed that CboK1 (α-KTx 10.5) and CboK2 (α-KTx 10.6) belong to the α-KTx 10.x subfamily, whereas CboK3 (α-KTx 2.22), CboK4 (α-KTx 2.23), CboK6 (α-KTx 2.21), and CboK7 (α-KTx 2.24) bear > 95% amino acid similarity with members of the α-KTx 2.x subfamily, and CboK5 is identical to Ce3 toxin (α-KTx 2.10). Electrophysiological assays demonstrated that except CboK1, all six other peptides blocked the Kv1.2 channel with Kd values in the picomolar range (24-763 pM) and inhibited the Kv1.3 channel with comparatively less potency (Kd values between 20-171 nM). CboK3 and CboK4 inhibited less than 10% and CboK7 inhibited about 42% of Kv1.1 currents at 100 nM concentration. Among all, CboK7 showed out-standing affinity for Kv1.2 (Kd = 24 pM), as well as high selectivity over Kv1.3 (850-fold) and Kv1.1 (~6000-fold). These characteristics of CboK7 may provide a framework for developing tools to treat Kv1.2-related channelopathies.
从墨西哥蝎子的毒液中分离得到 7 种新的肽，命名为 CboK1 到 CboK7，并测定了其一级结构。分子量在 3760.4 Da 到 4357.9 Da 之间，含有 32 到 39 个氨基酸残基，有 3 个潜在的二硫键。与已知钾蝎毒素 (KTx) 的氨基酸序列比较和系统发育分析表明，CboK1 (α-KTx 10.5) 和 CboK2 (α-KTx 10.6) 属于 α-KTx 10.x 亚家族，而 CboK3 (α-KTx 2.22)、CboK4 (α-KTx 2.23)、CboK6 (α-KTx 2.21) 和 CboK7 (α-KTx 2.24) 与 α-KTx 2.x 亚家族的成员具有 > 95%的氨基酸相似性，CboK5 与 Ce3 毒素 (α-KTx 2.10) 相同。电生理测定表明，除 CboK1 外，其余 6 种肽均以皮摩尔级（24-763 pM）的 Kd 值阻断 Kv1.2 通道，以相对较低的效力（Kd 值在 20-171 nM 之间）抑制 Kv1.3 通道。在 100 nM 浓度下，CboK3 和 CboK4 抑制 Kv1.1 电流不到 10%，CboK7 抑制约 42%。在所有这些肽中，CboK7 对 Kv1.2（Kd = 24 pM）具有显著的亲和力，对 Kv1.3（850 倍）和 Kv1.1（~6000 倍）具有高度选择性。CboK7 的这些特性可能为开发治疗 Kv1.2 相关通道病的工具提供了一个框架。
