Control of ion selectivity in LeuT:: Two Na+ binding sites with two different mechanisms
Control of ion selectivity in LeuT:: Two Na+ binding sites with two different mechanisms
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DOI：
10.1016/j.jmb.2008.01.015
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发表时间：
2008-03-28
影响因子：
5.6
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Noskov, Sergei Y.;Roux, Benoit
LeuT 是 Na+/Cl- 依赖性神经递质转运蛋白的细菌同源物，其 X 射线结构为更好地了解离子耦合转运蛋白中单价阳离子选择性的分子基础提供了很好的机会。 LeuT 拥有两个离子结合位点 NA1 和 NA2，对 Na+ 具有高度选择性。在不同温度和结合位点的不同占据状态下对嵌入显式膜中的 LeuT 进行广泛的全原子自由能分子动力学模拟，以剖析离子选择性的分子机制。结果表明，两个结合位点对 Na+ 表现出比 K+ 或 Li+（半径最相似的竞争离子）更强的选择性。特别有趣的是，主要负责两个结合位点选择性的机制似乎不同。在 NA1 中，Na+ 相对于 K+ 的选择性主要源于直接配位离子的亮氨酸底物带负电的羧酸根基团产生的强静电场。在仅包含中性配体的 NA2 中，对 Na+ 的选择性是通过氢键网络和围绕离子的多肽链的共价连接根据“紧密配合”机制产生的局部结构限制来增强的。 (C) 2008 Elsevier Ltd. 保留所有权利。
The x-ray structure of LeuT, a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters, provides a great opportunity to better understand the molecular basis of monovalent cation selectivity in ion-coupled transporters. LeuT possesses two ion binding sites, NA1 and NA2, which are highly selective for Na+. Extensive all-atom free-energy molecular dynamics simulations of LeuT embedded in an explicit membrane are performed at different temperatures and various occupancy states of the binding sites to dissect the molecular mechanism of ion selectivity. The results show that the two binding sites display robust selectivity for Na+ over K+ or Li+, the competing ions of most similar radii. Of particular interest, the mechanism primarily responsible for selectivity for each of the two binding sites appears to be different. In NA1, selectivity for Na+ over K+ arises predominantly from the strong electrostatic field arising from the negatively charged carboxylate group of the leucine substrate coordinating the ion directly. In NA2, which comprises only neutral ligands, selectivity for Na+ is enforced by the local structural restraints arising from the hydrogen-bonding network and the covalent connectivity of the polypeptide chain surrounding the ion according to a "snug-fit" mechanism. (C) 2008 Elsevier Ltd. All rights reserved.