Identification of the functional binding pocket for compounds targeting small-conductance Ca²⁺-activated potassium channels.
Identification of the functional binding pocket for compounds targeting small-conductance Ca²⁺-activated potassium channels.
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DOI：
10.1038/ncomms2017
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
小电导和中电导 Ca2+ 激活钾通道由 Ca2+ 结合钙调蛋白激活，在调节膜兴奋性中发挥重要作用。这些通道也与临床异常有关。人们投入了大量的精力来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，阻碍了它们的临床应用潜力。一个关键的影响因素是缺乏对这些化合物的结合位点的了解。在这里，我们通过 X 射线晶体学证明 1-EBIO 类化合物的结合口袋位于钙调蛋白通道界面。我们证明，基于结构数据和分子对接，通道突变可以有效改变这些化合物的效力。我们的结果深入了解了结合袋的分子性质及其对 1-EBIO 类化合物的效力和选择性的贡献。
Small- and intermediate-conductance Ca2+-activated potassium channels, activated by Ca2+-bound calmodulin, play 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 potentials 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-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.
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影响因子：
2.9
作者：
Armen, Roger S.;Schiller, Stefan M.;Brooks, Charles L., III
通讯作者：
Brooks, Charles L., III
影响因子：
30.8
作者：
Ellinor, Patrick T.;Lunetta, Kathryn L.;Glazer, Nicole L.;Pfeufer, Arne;Alonso, Alvaro;Chung, Mina K.;Sinner, Moritz F.;de Bakker, Paul I. W.;Mueller, Martina;Lubitz, Steven A.;Fox, Ervin;Darbar, Dawood;Smith, Nicholas L.;Smith, Jonathan D.;Schnabel, Renate B.;Soliman, Elsayed Z.;Rice, Kenneth M.;Van Wagoner, David R.;Beckmann, Britt-M;van Noord, Charlotte;Wang, Ke;Ehret, Georg B.;Rotter, Jerome I.;Hazen, Stanley L.;Steinbeck, Gerhard;Smith, Albert V.;Launer, Lenore J.;Harris, Tamara B.;Makino, Seiko;Nelis, Mari;Milan, David J.;Perz, Siegfried;Esko, Tonu;Koettgen, Anna;Moebus, Susanne;Newton-Cheh, Christopher;Li, Man;Moehlenkamp, Stefan;Wang, Thomas J.;Kao, W. H. Linda;Vasan, Ramachandran S.;Noethen, Markus M.;MacRae, Calum A.;Stricker, Bruno H. Ch;Hofman, Albert;Uitterlinden, Andre G.;Levy, Daniel;Boerwinkle, Eric;Metspalu, Andres;Topol, Eric J.;Chakravarti, Aravinda;Gudnason, Vilmundur;Psaty, Bruce M.;Roden, Dan M.;Meitinger, Thomas;Wichmann, H-Erich;Witteman, Jacqueline C. M.;Barnard, John;Arking, Dan E.;Benjamin, Emelia J.;Heckbert, Susan R.;Kaeaeb, Stefan
通讯作者：
Kaeaeb, Stefan
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M