Abstract

In mammals, about 40 isoforms of voltage-gated potassium channels (K_Vs) have been found. To study such a variety of K_Vs, substances are needed that are able to selectively bind to them and change their properties. We have previously reported on the isolation and pharmacological characterization of MeKTx13-3, a peptide toxin from the venom of the scorpion Mesobuthus eupeus. The toxin has shown high affinity to a number of K_Vs, with little selectivity for the K_V1.1 isoform. In this paper, we describe the production of an artificial derivative of MeKTx13-3, named MeKTx13-3_RMRH, using rational design. The selectivity of MeKTx13-3_RMRH in relation to K_V1.1 is increased by an order of magnitude making it one of the most specific ligands of this K_V isoform. Finally, using computer simulations, we demonstrate that the preference of the new ligand to K_V1.1 can be realized through a specific positioning of the toxin in complex with the channel.

中文翻译：

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高选择性钾通道KV 1.1的人工肽配体

摘要

在哺乳动物中，已发现约40种电压门控钾通道（K _V s）的同工型。为了研究各种各样的K _V s，需要能够选择性结合它们并改变其性质的物质。我们以前曾报道过MeKTx13-3的分离和药理学表征，MeKTx13-3是一种从蝎美索不达斯蝎的毒液中提取的肽毒素。该毒素对许多K _V s表现出高亲和力，对K _V 1.1同工型的选择性很小。在本文中，我们使用合理的设计描述了MeKTx13-3的人工衍生物MeKTx13-3_RMRH的生产。MeKTx13-3_RMRH相对于K _V的选择性1.1增加一个数量级，使其成为该K _V同工型的最特异的配体之一。最后，通过计算机模拟，我们证明了新配体对K _V 1.1的偏爱可以通过毒素与通道复合的特定定位来实现。