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Mechanisms Underlying the Inhibition of KV1.3 Channel by Scorpion Toxin ImKTX58
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2022-09-01 , DOI: 10.1124/molpharm.121.000480 Xu Zhang 1 , Qianru Zhao 1 , Fan Yang 1 , Zhen Lan 1 , Yi Li 1 , Min Xiao 1 , Hui Yu 1 , Ziyi Li 1 , Yongsheng Zhou 1 , Yingliang Wu 1 , Zhijian Cao 1 , Shijin Yin 2
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2022-09-01 , DOI: 10.1124/molpharm.121.000480 Xu Zhang 1 , Qianru Zhao 1 , Fan Yang 1 , Zhen Lan 1 , Yi Li 1 , Min Xiao 1 , Hui Yu 1 , Ziyi Li 1 , Yongsheng Zhou 1 , Yingliang Wu 1 , Zhijian Cao 1 , Shijin Yin 2
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Voltage-gated KV1.3 channel has been reported to be a drug target for the treatment of autoimmune diseases, and specific inhibitors of Kv1.3 are potential therapeutic drugs for multiple diseases. The scorpions could produce various bioactive peptides that could inhibit KV1.3 channel. Here, we identified a new scorpion toxin polypeptide gene ImKTX58 from the venom gland cDNA library of the Chinese scorpion Isometrus maculatus. Sequence alignment revealed high similarities between ImKTX58 mature peptide and previously reported KV1.3 channel blockers—LmKTX10 and ImKTX88—suggesting that ImKTX58 peptide might also be a KV1.3 channel blocker. By using electrophysiological recordings, we showed that recombinant ImKTX58 prepared by genetic engineering technologies had a highly selective inhibiting effect on KV1.3 channel. Further alanine scanning mutagenesis and computer simulation identified four amino acid residues in ImKTX58 peptide as key binding sites to KV1.3 channel by forming hydrogen bonds, salt bonds, and hydrophobic interactions. Among these four residues, 28th lysine of the ImKTX58 mature peptide was found to be the most critical amino acid residue for blocking KV1.3 channel.
更新日期：2022-08-19
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