'C-type' closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel.
'C-type' closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel.
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TREK-1通道的构象变化揭示了K2P通道的C型关闭状态和门控机制
DOI：
10.1093/jmcb/mjac002
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发表时间：
2022-04-21
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
双孔结构域钾（K2 P）通道门控主要在选择性过滤器内，称为“C型”门控。由于缺乏对非导电（闭合）状态的结构见解，“C型”门控机制仍然难以捉摸。在这里，对TREK-1（一种K2 P通道）的分子动力学（MD）模拟显示，M4螺旋运动以一种代表“C型”闭合状态的新型“更深”结构诱导过滤器闭合。"下“结构并不代表先前提出的关闭状态，而是作为门控中的中间状态。该研究确定了M4螺旋运动在调节过滤器关闭中的变构“跷跷板”机制。最后，在这种对K2 P门控机制的认识的指导下，MD模拟揭示了功能获得性突变和小分子激活剂通过扰动从开放状态到闭合状态的状态转变来激活TREK-1。总之，我们揭示了一个“C型”的封闭状态，并提供机械的见解门控程序和变构调节K2 P通道。
Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanisms remain elusive. Here, molecular dynamics (MD) simulations on TREK-1, a K2P channel, revealed that M4 helix movements induce filter closing in a novel ‘deeper-down’ structure that represents a ‘C-type’ closed state. The ‘down’ structure does not represent the closed state as previously proposed and instead acts as an intermediate state in gating. The study identified the allosteric ‘seesaw’ mechanism of M4 helix movements in modulating filter closing. Finally, guided by this recognition of K2P gating mechanisms, MD simulations revealed that gain-of-function mutations and small-molecule activators activate TREK-1 by perturbing state transitions from open to closed states. Together, we reveal a ‘C-type’ closed state and provide mechanical insights into gating procedures and allosteric regulations for K2P channels.
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影响因子：
64.8
作者：
Li B;Rietmeijer RA;Brohawn SG
通讯作者：
Brohawn SG
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
4.6
作者：
Harrigan MP;McKiernan KA;Shanmugasundaram V;Denny RA;Pande VS
通讯作者：
Pande VS
k（2p）2.1（Trek-1） - 激活器复合物揭示了一个隐秘的选择性滤波器结合位点。
影响因子：
64.8
作者：
Lolicato M;Arrigoni C;Mori T;Sekioka Y;Bryant C;Clark KA;Minor DL Jr
通讯作者：
Minor DL Jr
DOI：
10.1016/j.str.2017.03.006
发表时间：
2017-05-02
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Aryal P;Jarerattanachat V;Clausen MV;Schewe M;McClenaghan C;Argent L;Conrad LJ;Dong YY;Pike ACW;Carpenter EP;Baukrowitz T;Sansom MSP;Tucker SJ
通讯作者：
Tucker SJ