RT Journal Article
SR Electronic
T1 Mechanisms Underlying the Inhibition of KV1.3 Channel by Scorpion Toxin ImKTX58
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 150
OP 160
DO 10.1124/molpharm.121.000480
VO 102
IS 3
A1 Xu Zhang
A1 Qianru Zhao
A1 Fan Yang
A1 Zhen Lan
A1 Yi Li
A1 Min Xiao
A1 Hui Yu
A1 Ziyi Li
A1 Yongsheng Zhou
A1 Yingliang Wu
A1 Zhijian Cao
A1 Shijin Yin
YR 2022
UL http://molpharm.aspetjournals.org/content/102/3/150.abstract
AB 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.SIGNIFICANCE STATEMENT In this study, we discovered a scorpion toxin gene ImKTX58 that has not been reported before in Hainan Isometrus maculatus and successfully used the prokaryotic expression system to express and purify the polypeptides encoded by this gene. Electrophysiological experiments on ImKTX58 showed that ImKTX58 has a highly selective blocking effect on KV1.3 channel over Kv1.1, Kv1.2, Kv1.5, SK2, SK3, and BK channels. These findings provide a theoretical basis for designing highly effective KV1.3 blockers to treat autoimmune and other diseases.