Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.
Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.
复制标题
配体诱导的循环核苷酸调节钾通道MLOK1的结构变化。
DOI：
10.1038/ncomms4106
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发表时间：
2014
影响因子：
16.6
通讯作者：
Stahlberg, Henning
中科院分区：
文献类型：
--
作者：
Kowal, Julia;Chami, Mohamed;Baumgartner, Paul;Arheit, Marcel;Chiu, Po-Lin;Rangl, Martina;Scheuring, Simon;Schroeder, Gunnar F.;Nimigean, Crina M.;Stahlberg, Henning
环核苷酸调节离子通道在真核生物的信号转导和起搏中起着重要的作用。这些通道中配体门控的分子决定因素仍然未知，主要是因为缺乏直接的结构信息。在这里，我们报告了配体诱导的全长MloK1构象变化，这是一种来自中根菌的环核苷酸调制的钾通道，通过电子晶体学和原子力显微镜进行了分析。cAMP结合后，环核苷酸结合结构域垂直向膜方向移动，直接接触S1-S4电压传感器结构域。这伴随着电压传感器域螺旋的显著移位和倾斜。在这两种状态下，内层孔衬螺旋呈“开放”构象。我们提出了一种机制，其中配体结合可以通过环核苷酸结合域和电压传感器之间的直接相互作用促进孔打开。这为真核HCN通道中配体门控和电压感应之间的耦合提供了一个简单的机制假设。环核苷酸调节离子通道配体门控的分子决定因素尚不清楚。Kowal等人确定了cAMP与细菌通道MloK1结合的构象变化，并提出了真核HCN通道中配体门控和电压传感耦合的机制。
Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1–S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an ‘open’ conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels. The molecular determinants underlying ligand gating of cyclic nucleotide-modulated ion channels remain unclear. Kowal et al. determine the conformational changes underlying cAMP binding to the bacterial channel MloK1, and propose a mechanism for coupling of ligand gating and voltage sensing in eukaryotic HCN channels.
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DOI：
10.1073/pnas.0711533105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Clayton, Gina M.;Altieri, Steve;Morais-Cabral, Joao H.
通讯作者：
Morais-Cabral, Joao H.
影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
5.6
作者：
Altieri, Stephen L.;Clayton, Gina M.;Morais-Cabral, Joao H.
通讯作者：
Morais-Cabral, Joao H.
影响因子：
3
作者：
Crowther, RA;Henderson, R;Smith, JM
通讯作者：
Smith, JM
影响因子：
5.6
作者：
Appel, Matthias;Hizlan, Dilem;Kuehlbrandt, Werner
通讯作者：
Kuehlbrandt, Werner