<br>深入了解大型中性氨基酸转运蛋白 1 (LAT1) 的结构、功能和配体发现。,International Journal of Molecular Sciences

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深入了解大型中性氨基酸转运蛋白 1 (LAT1) 的结构、功能和配体发现。
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2018-04-24 , DOI: 10.3390/ijms19051278
Natesh Singh ₁ , Gerhard F Ecker ₁

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大中性氨基酸转运蛋白 1（LAT1 或 SLC7A5）是一种不依赖钠和 pH 的转运蛋白，为细胞提供必需氨基酸（例如亮氨酸、苯丙氨酸）。它在血脑屏障 (BBB) 中发挥着重要作用，促进甲状腺激素、药物（例如左旋多巴、加巴喷丁）和代谢物转运至大脑。此外，其表达在各种类型的人类癌症中高度上调，这些癌症的特征是生长和增殖对氨基酸的强烈需求。因此，LAT1被认为是癌症治疗的重要药物靶点。随着大肠杆菌中精氨酸/胍丁胺逆向转运蛋白 (AdiC) 的结晶，建立了许多 LAT1 同源模型来阐明底物结合位点、配体转运蛋白相互作用和结构功能关系。这些模型与分子对接和实验测试相结合的使用已经确定了 LAT1 配体的新化学型。在这里，我们重点介绍 LAT1 的结构、功能、运输机制和同源建模。此外，还解决了对 LAT1 进行的结构功能研究的结果，这增强了我们对底物结合和易位机制的了解。随后讨论了基于配体和结构的方法，重点是阐明 LAT1 抑制的分子基础。最后，我们对迄今为止已发现的不同 LAT1 抑制剂进行了详尽的总结，包括最近发现的不可逆共价抑制剂。

"点击查看英文标题和摘要"

Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1.

The large neutral amino acid transporter 1 (LAT1, or SLC7A5) is a sodium- and pH-independent transporter, which supplies essential amino acids (e.g., leucine, phenylalanine) to cells. It plays an important role at the Blood⁻Brain Barrier (BBB) where it facilitates the transport of thyroid hormones, pharmaceuticals (e.g., l-DOPA, gabapentin), and metabolites into the brain. Moreover, its expression is highly upregulated in various types of human cancer that are characterized by an intense demand for amino acids for growth and proliferation. Therefore, LAT1 is believed to be an important drug target for cancer treatment. With the crystallization of the arginine/agmatine antiporter (AdiC) from Escherichia Coli, numerous homology models of LAT1 have been built to elucidate the substrate binding site, ligand⁻transporter interaction, and structure⁻function relationship. The use of these models in combination with molecular docking and experimental testing has identified novel chemotypes of ligands of LAT1. Here, we highlight the structure, function, transport mechanism, and homology modeling of LAT1. Additionally, results from structure⁻function studies performed on LAT1 are addressed, which have enhanced our knowledge of the mechanism of substrate binding and translocation. This is followed by a discussion on ligand- and structure-based approaches, with an emphasis on elucidating the molecular basis of LAT1 inhibition. Finally, we provide an exhaustive summary of different LAT1 inhibitors that have been identified so far, including the recently discovered irreversible covalent inhibitors.

更新日期：2019-11-01

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