Structure-Based Identification of Inhibitors for the SLC13 Family of Na(+)/Dicarboxylate Cotransporters.
Structure-Based Identification of Inhibitors for the SLC13 Family of Na(+)/Dicarboxylate Cotransporters.
复制标题
基于结构的 Na(+)/二羧酸协同转运蛋白 SLC13 家族抑制剂的鉴定。
DOI：
10.1021/acs.biochem.5b00388
复制
发表时间：
2015-08-11
期刊：
影响因子：
2.9
通讯作者：
Schlessinger A
中科院分区：
文献类型：
--
作者：
Colas C;Pajor AM;Schlessinger A
在哺乳动物中，柠檬酸循环中间体在调节脂肪酸合成和糖酵解等多种代谢过程中发挥关键作用。钠依赖性SLC13转运蛋白家族的成员介导二羧酸和三羧酸进入细胞的转运。SLC13成员与寿命延长和对高脂肪饮食的抵抗有关，因此，它们是治疗衰老和代谢紊乱的新药物靶点。我们之前使用同源模型表征了人类NaDC3/SLC13A3转运体底物和阳离子结合的关键结构决定因素。在这里，我们将计算建模和虚拟筛选与功能和生化测试相结合，从人和小鼠中鉴定出9种以前未知的SLC13家族多个成员的抑制剂。我们的研究结果揭示了SLC13家族之前未知的底物选择性决定因素，包括介导配体结合和运输的关键残基，以及混杂和特异性SLC13小分子配体。新发现的配体可以作为进一步表征SLC13家族的化学工具，或作为未来开发治疗代谢疾病和衰老的有效抑制剂的先导分子。我们的研究结果提高了我们对结构成分的理解，这些结构成分在这个生理上重要的家族以及其他结构相关的运输系统中对底物特异性很重要。
In mammals, citric acid cycle intermediates play a key role in regulating various metabolic processes, such as fatty acid synthesis and glycolysis. Members of the sodium dependent SLC13 transporter family mediate the transport of di and tricarboxylates into cells. SLC13 members have been implicated in lifespan extension and resistance to high fat diets, thus, they are emerging drug targets for aging and metabolic disorders. We previously characterized key structural determinants of substrate and cation binding for the human NaDC3/SLC13A3 transporter using a homology model. Here, we combine computational modeling and virtual screening with functional and biochemical testing, to identify 9 previously unknown inhibitors for multiple members of the SLC13 family from human and mouse. Our results reveal previously unknown substrate selectivity determinants for the SLC13 family, including key residues that mediate ligand binding and transport, as well as promiscuous and specific SLC13 small molecule ligands. The newly discovered ligands can serve as chemical tools to further characterize the SLC13 family or as lead molecules for future development of potent inhibitors for the treatment of metabolic diseases and aging. Our results improve our understanding of the structural components that are important for substrate specificity in this physiologically important family as well as in other structurally related transport systems.