Monoamine transporters: insights from molecular dynamics simulations.
Monoamine transporters: insights from molecular dynamics simulations.
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DOI：
10.3389/fphar.2015.00235
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发表时间：
2015
影响因子：
5.6
通讯作者：
Schiøtt B
中科院分区：
文献类型：
--
作者：
Grouleff J;Ladefoged LK;Koldsø H;Schiøtt B
人类单胺转运蛋白（MAT）促进神经递质5-羟色胺、多巴胺和去甲肾上腺素从突触间隙的再摄取。单胺能神经传递的不平衡与各种疾病有关，包括重度抑郁症、注意缺陷多动障碍、精神分裂症和帕金森病。因此，抑制MAT是治疗此类疾病的重要策略。MAT是属于神经递质/Na+同向转运体（NSS）家族的钠偶联转运蛋白，并且2005年NSS家族成员细菌亮氨酸转运体LeuT的第一个高分辨率结构的出版物被证明是理解该转运体家族的主要垫脚石。结构数据允许使用计算方法来研究MAT，这反过来又导致了一些重要的发现。底物跨膜转运的过程是一个内在的动态过程。分子动力学模拟可以提供ns到ms时间尺度上分子运动的原子细节，因此非常适合研究输运过程。在这篇综述中，我们概述了分子动力学模拟如何提供洞察与运输的神经递质，以及外部和内部的门的存在下，离子和底物之间的耦合运输，和底物和抑制剂诱导的构象变化的差异相关的大规模运动。
The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson’s disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors.