Structural Basis for Differences in Dynamics Induced by Leu Versus Ile Residues in the CD Loop of Kir Channels.
Structural Basis for Differences in Dynamics Induced by Leu Versus Ile Residues in the CD Loop of Kir Channels.
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DOI：
10.1007/s12035-015-9466-x
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发表时间：
2016-11
影响因子：
5.1
通讯作者：
Long, Mian
中科院分区：
文献类型：
--
作者：
Lu, Shouqin;An, Hailong;Zhang, Hailin;Long, Mian
关键词：
CD环中保守的Leu/Ile位对KIR通道的门控动力学以及相应的微结构机制的影响尚不清楚。通过分子动力学模拟研究了鸡肉Kir2.2的结构机理。与WT相比，I223L突变通道与PIP2结合更强，激活更快，在PIP2解离后保持更稳定的激活状态。小鼠Kir2.1和人Kir2.2的细胞电生理分析表明，与模拟一致，Leu残基通过增加结合亲和力和更快的激活动力学来增加对PIP2的通道反应，而在PIP2抑制时，失活动力学降低。Ile残基诱导了相反的反应。这种差异归因于Leu和Ile不同的疏水侧链对称性；在这些残基之间切换导致相互作用网络重新分布，并在Leu系统中提供有效的构象转导，因为Leu系统具有更多刚性和独立的亚基。本文的在线版本(doi：10.1007/s12035-0159466-x)包含补充材料，授权用户可以使用。
The effect of the conserved Leu/Ile site in the CD loop on the gating dynamics of Kir channels and corresponding micro-structural mechanism remains unclear. Molecular dynamics simulations were performed to investigate the structural mechanism of chicken Kir2.2. Compared to WT, the I223L mutant channel bound to PIP2 more strongly, was activated more rapidly, and maintained the activation state more stably after PIP2 dissociation. Cellular electrophysiology assays of mouse Kir2.1 and human Kir2.2 indicated that, consistent with simulations, the Leu residue increased the channel responses to PIP2 through increased binding affinity and faster activation kinetics, and the deactivation kinetics decreased upon PIP2 inhibition. The Ile residue induced the opposite responses. This difference was attributed to the distinct hydrophobic side chain symmetries of Leu and Ile; switching between these residues caused the interaction network to redistribute and offered effective conformation transduction in the Leu systems, which had more rigid and independent subunits. The online version of this article (doi:10.1007/s12035-015-9466-x) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Hansen, Scott B.;Tao, Xiao;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
影响因子：
25
作者：
Pegan, S;Arrabit, C;Choe, S
通讯作者：
Choe, S
影响因子：
4.8
作者：
D'Avanzo, Nazzareno;Lee, Sun-Joo;Nichols, Colin G.
通讯作者：
Nichols, Colin G.
影响因子：
4.8
作者：
Du, XO;Zhang, HL;Logothetis, DE
通讯作者：
Logothetis, DE
DOI：
10.1126/science.1180310
发表时间：
2009-12-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tao X;Avalos JL;Chen J;MacKinnon R
通讯作者：
MacKinnon R