Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Robert-Koch-Str. 45, Münster, Germany.
Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstr. 48, Münster, Germany.
Commun Biol. 2023 Jul 18;6(1):745. doi: 10.1038/s42003-023-05114-4.
The TWIK-related spinal cord K channel (TRESK, K18.1) is a K channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological TRESK function was identified as a key player in T-cell differentiation rendering the channel a new pharmacological target for treatment of autoimmune diseases. The channel activator cloxyquin represents a promising lead compound for the development of a new class of immunomodulators. Identification of cloxyquin binding site and characterization of the molecular activation mechanism can foster the future drug development. Here, we identify the cloxyquin binding site at the M2/M4 interface by mutational scan and analyze the molecular mechanism of action by protein modeling as well as in silico and in vitro electrophysiology using different permeating ion species (K / Rb). In combination with kinetic analyses of channel inactivation, our results suggest that cloxyquin allosterically stabilizes the inner selectivity filter facilitating the conduction process subsequently activating hTRESK.
TWIK 相关的脊髓钾通道（TRESK，K18.1）是一种钾通道，有助于维持各种细胞的膜电位。最近，生理 TRESK 功能被确定为 T 细胞分化的关键参与者，使该通道成为治疗自身免疫性疾病的新的药理学靶标。通道激活剂氯喹啉代表了一类新的免疫调节剂发展的有前途的先导化合物。鉴定氯喹啉结合位点并阐明分子激活机制可以促进未来的药物开发。在这里，我们通过突变扫描确定了 M2/M4 界面处的氯喹啉结合位点，并通过蛋白建模以及使用不同渗透离子种类（K / Rb）的计算机模拟和体外电生理学分析了作用机制。结合通道失活的动力学分析，我们的结果表明，氯喹啉变构稳定了内选择性过滤器，从而促进了随后激活 hTRESK 的传导过程。
