SLC Transporters: Structure, Function, and Drug Discovery.
SLC Transporters: Structure, Function, and Drug Discovery.
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DOI：
10.1039/c6md00005c
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Schlessinger A
中科院分区：
文献类型：
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作者：
Colas C;Ung PM;Schlessinger A
人溶质载体（SLC）转运蛋白是药物开发的重要靶点。基于结构的药物发现SLC转运蛋白需要描述其结构，动力学和与小分子配体和离子相互作用的机制。最近确定的人SLC转运蛋白及其同系物的原子结构，结合改进的计算能力和预测方法，导致了基于结构的药物设计方法对人SLC成员的适用性增加。本文就SLC转运蛋白的结构和转运机制作一综述。然后，我们描述了计算技术，如同源性建模和虚拟筛选，是新兴的关键工具，发现人类SLC成员的化学探针。我们说明了这些方法的实用性，提出的案例研究中，合理整合的计算和实验被用来表征SLC成员，运输关键的营养物质和代谢产物，包括氨基酸转运蛋白LAT-1和ASCT 2，SLC 13家族的柠檬酸循环中间转运蛋白，和葡萄糖转运蛋白GLUT 1。最后，我们简要讨论了未来的方向，在基于结构的药物发现的人类SLC超家族，在人类中最具结构和功能多样性的蛋白质家族之一。
The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters’ structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.