Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease
Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease
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专为 Kv1.3 通道（自身免疫性疾病的治疗靶点）设计的强效肽抑制剂的结构基础。
DOI：
10.1074/jbc.m802054200
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发表时间：
2008-07-04
影响因子：
4.8
通讯作者：
Li, Wen-Xin
中科院分区：
文献类型：
--
作者：
Han, Song;Yi, Hong;Li, Wen-Xin
钾通道Kv1.3是T细胞介导的自身免疫性疾病的免疫调节的有吸引力的药理学靶点。Kv1.3的有效和选择性阻断剂是治疗这些疾病的潜在疗法。在这里，我们描述了一种新的肽抑制剂，是有效的和选择性的Kv1.3的设计。将蝎毒素BmKTX的三个残基（Gly（11），Ile（28），Asp（33））分别替换为Arg（11），Thr（28），His（33），得到一个新的多肽，命名为ADWX-1。ADWX-1肽以皮摩尔亲和力（IC 50，1.89 pM）阻断Kv1.3，与天然BmKTX毒素相比，活性增加了100倍。ADWX-1对Kv1.3通道的选择性也优于Kv1.1和Kv1.2通道。此外，进行丙氨酸扫描突变以定位ADWX-1在阻断Kv1.3中的功能残基。此外，计算模拟被用来建立ADWX-1-Kv1.3复杂的结构模型。该模型表明，所有突变的残基都有利于ADWX-1对Kv1.3的高效力和选择性。在Kv1.3中，ADWX-1的Arg 11与Asp 386相互作用，而ADWX-1的Thr 28和His 33位于Kv1.3的选择性过滤器-S6接头的正上方。总之，我们的数据表明，特定的ADWX-1肽将是T细胞介导的自身免疫性疾病的治疗中的一个可行的领导，ADWX-1的成功设计表明，基于肽通道复合物的结构模型的合理设计应该加速人类通道病的诊断和治疗剂的发展。
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 (Gly(11), Ile(28), and Asp(33)) of a scorpion toxin BmKTX were substituted by Arg(11), Thr(28), and His(33), 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.