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A novel spider toxin as a selective antagonist of the Kv1 subfamily of voltage-gated potassium channels through gating modulation

文献类型： 外文期刊

作者： Xiao, Zhen 1 ; You, Xia 1 ; Chen, Minzhi 1 ; Li, Huazhen 1 ; Chen, Bo 5 ; Hu, Zhaotun 5 ; You, Qian 1 ; Liu, Hongrong 3 ; Zhao, Piao 1 ; Zhou, Xi 1 ; Liu, Zhonghua 1 ;

作者机构： 1.Hunan Normal Univ, Coll Life Sci, Natl & Local Joint Engn Lab Anim Peptide Drug Dev, Changsha, Peoples R China

2.Hunan Normal Univ, Furong Lab, Peptide & Small Mol Drug R&D Platform, Changsha, Peoples R China

3.Hunan Normal Univ, Inst Interdisciplinary Studies, Changsha, Peoples R China

4.Hunan Normal Univ, Sch Phys & Elect, Key Lab Matter Microstruct & Funct Hunan Prov, Key Lab Low Dimens Quantum Struct & Quantum Contro, Changsha, Peoples R China

5.Huaihua Univ, Coll Biol & Food Engn, Key Lab Res & Utilizat Ethnomedicinal Plant Resour, Huaihua, Peoples R China

6.Hunan Acad Agr Sci, Inst Plant Protect, Changsha, Peoples R China

7.Hunan Prov Key Lab Pesticide Biol & Precise Use Te, Changsha, Peoples R China

期刊名称：JOURNAL OF BIOLOGICAL CHEMISTRY （ 影响因子：3.9； 五年影响因子：4.3 ）

ISSN：

年卷期： 2025 年 301 卷 4 期

页码：

收录情况： SCI

摘要： Members of the voltage-gated potassium channel subfamily (Kv1) are essential for the nervous and immune systems, necessitating novel modulators and deeper insights into their structure-function relationships. While all known peptide inhibitors targeting Kv1 channels are pore blockers, we identified MrVIII (K-HxTx-MrVIII), a novel peptide toxin from the venom of spider Macrothele raveni, as the first voltage-gating modifier antagonist with selective activity against Kv1 channels. MrVIII exhibits high-affinity inhibition of Kv1.2, Kv1.3, Kv1.5, and Kv1.6, completely suppressing their currents. By contrast, it selectively inhibits the initial activation phase of Kv1.1, Kv1.4, and Kv1.7 with lower affinity, reflecting its differential subtype modulation. Gating current analyses revealed that MrVIII stabilizes the voltage sensor of Kv1 channels in its resting state, thereby preventing activation upon depolarization. The interaction between MrVIII and Kv1.1, Kv1.4, and Kv1.7 is unstable, with the voltage sensor of Kv1.7, initially stabilized in the resting state by the toxin, potentially transitioning back to an activated state, influenced by the strength and duration of depolarization. Alanine-scanning mutagenesis identified the S3-S4 region as the critical interaction region, with the conserved residue Y339 (in Kv1.3) serving as a key binding site across subtypes. Additionally, the contribution of E283 and T286 in Kv1.1 and A256 in Kv1.7 are key residues in defining channel's pattern in inhibition by MrVIII, compared to Kv1.3. These findings establish MrVIII as a valuable molecular tool for studying Kv1 channels, offering potential pathways for drug development and therapeutic applications.

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