Probing dopamine transporter structure and function by Zn2+-site engineering
Probing dopamine transporter structure and function by Zn2+-site engineering
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DOI：
10.1016/j.ejphar.2003.08.068
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发表时间：
2003-10-31
影响因子：
5
通讯作者：
Gether, U
中科院分区：
文献类型：
--
作者：
Loland, CJ;Norgaard-Nielsen, K;Gether, U
生物胺转运体属于Na+/Cl-偶联溶质载体，包括多巴胺(DAT)、去甲肾上腺素(NET)和5-羟色胺(SERT)转运体。这些转运体是许多精神活性化合物作用的主要目标，包括最常用的抗抑郁药以及被广泛滥用的药物，如可卡因和苯丙胺。尽管它们具有重要的药理作用，但人们对它们的高级结构组织和底物转运过程中的分子机制知之甚少。在这篇综述中，我们将描述我们如何利用锌离子结合位点作为工具来探索Na+/Cl-偶联的生物胺转运蛋白的结构和功能，尤其是人类DAT(HDAT)。这项工作不仅定义了这类转运蛋白的三级结构中的第一个结构约束，而且还允许推断伴随底物转运的构象变化和对调节运输周期中不同功能状态之间的平衡至关重要的残基。(C)2003爱思唯尔B.V.保留所有权利。
The biogenic amine transporters belong to the class of Na+/Cl--coupled solute carriers and include the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT). These transporters are the primary targets for the action of many psychoactive compounds including the most commonly used antidepressants as well as widely abused drugs such as cocaine and amphetamines. In spite of their pharmacological importance, still little is known about their higher structural organization and the molecular mechanisms underlying the substrate translocation process. In this review, it will be described how we have used Zn2+-binding sites as a tool to probe the structure and function of Na+/Cl--coupled biogenic amine transporters with specific focus on the human DAT (hDAT). The work has not only led to the definition of the first structural constrains in the tertiary structure of this class of transporters, but also allowed inferences about conformational changes accompanying substrate translocation and residues critical for regulating the equilibrium between different functional states in the transport cycle. (C) 2003 Elsevier B.V. All rights reserved.