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J. Biol. Chem., Vol. 283, Issue 27, 19058-19065, July 4, 2008

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Structural Basis of a Potent Peptide Inhibitor Designed for Kv1.3 Channel, a Therapeutic Target of Autoimmune Disease^*

From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China

The potassium channel Kv1.3 is an attractive pharmacological target for immunomodulation of T cell-mediated autoimmune diseases. Potent and selective blockers of Kv1.3 are potential therapeutics for treating these diseases. Here we describe the design of a new peptide inhibitor that is potent and selective for Kv1.3. Three residues (Gly¹¹, Ile²⁸, and Asp³³) of a scorpion toxin BmKTX were substituted by Arg¹¹, Thr²⁸, and His³³, resulting in a new peptide, named ADWX-1. The ADWX-1 peptide blocked Kv1.3 with picomolar affinity (IC₅₀, 1.89 pM), showing a 100-fold increase in activity compared with the native BmKTX toxin. The ADWX-1 also displayed good selectivity on Kv1.3 over related Kv1.1 and Kv1.2 channels. Furthermore, alanine-scanning mutagenesis was carried out to map the functional residues of ADWX-1 in blocking Kv1.3. Moreover, computational simulation was used to build a structural model of the ADWX-1-Kv1.3 complex. This model suggests that all mutated residues are favorable for both the high potency and selectivity of ADWX-1 toward Kv1.3. While Arg¹¹ of ADWX-1 interacts with Asp³⁸⁶ in Kv1.3, Thr²⁸ and His³³ of ADWX-1 locate right above the selectivity filter-S6 linker of Kv1.3. Together, our data indicate that the specific ADWX-1 peptide would be a viable lead in the therapy of T cell-mediated autoimmune diseases, and the successful design of ADWX-1 suggests that rational design based on the structural model of the peptide-channel complex should accelerate the development of diagnostic and therapeutic agents for human channelopathies.

Received for publication, March 14, 2008 , and in revised form, May 9, 2008.

^* This work was supported in part by Grants from the National Natural Sciences Foundation of China (30530140, 30570045, and 30770519) and the Ministry of Education Foundation of China (106108). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China. Tel.: 86-0-27-68752831; Fax: 86-0-27-68752146; E-mail: ylwu{at}whu.edu.cn.

³ To whom correspondence may be addressed: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China. Tel.: 86-0-27-68752831; Fax: 86-0-27-68752146; E-mail: liwxlab{at}whu.edu.cn.

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