Department of Molecular Physiology and Biophysics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA.
Nat Commun. 2012;3:1021. doi: 10.1038/ncomms2017.
Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class.
小电导和中等电导钙激活钾通道，由结合钙调蛋白的 Ca(2+) 激活，在调节膜兴奋性方面发挥重要作用。这些通道也与临床异常有关。研究人员投入了大量精力开发针对这些通道的小分子化合物。然而，这些化合物往往效力低且缺乏选择性，阻碍了它们在临床应用中的潜力。一个关键的促成因素是缺乏这些化合物结合位点的知识。在这里，我们通过 X 射线晶体学证明，1-乙基-2-苯并咪唑啉酮（1-EBIO）类化合物的结合口袋位于钙调蛋白-通道界面。我们表明，基于结构数据和分子对接，通道的突变可以有效地改变这些化合物的效力。我们的结果提供了对结合口袋的分子性质及其对 1-EBIO 类化合物效力和选择性的贡献的深入了解。
