The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases.
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K⁺ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the "evolutionary" Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel-specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. fang.ye@whu.edu.cn.
Fang
F
Ye
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. ythu@sjtu.edu.cn.
Youtian
Y
Hu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Xrz-287@whu.edu.cn.
Weiwei
W
Yu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. zlxie@whu.edu.cn.
Zili
Z
Xie
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Herohugo555@whu.edu.cn.
Jun
J
Hu
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. zjcao@whu.edu.cn.
Zhijian
Z
Cao
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. liwxlab@whu.edu.cn.
Wenxin
W
Li
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. ylwu@whu.edu.cn.
Yingliang
Y
Wu
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases; D017252:CD3 Complex; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000502:physiology*; D010047:Ovalbumin; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011917:Rats, Inbred Lew; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012605:Scorpions; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D017252:CD3 Complex; D016207:Cytokines; D007155:Immunologic Factors; C109066:KTX toxin, Buthus; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D010047:Ovalbumin
BmKTX; BmKTX-D33H; Kv1.3 channel; autoimmune diseases; ion channel selectivity; scorpion toxin