PDF(Pubmed)
Abstract：
The taurine transporter (TauT, SLC6A6) is a member of the solute carrier 6 (SLC6) family, which plays multiple physiological roles. The SLC6 family is divided into four subfamilies: GABA (γ-aminobutyric acid), monoamine, glycine and neutral amino acid transporters. Proteins from the GABA group, including the taurine transporter, are primarily considered therapeutic targets for treating central nervous system disorders. However, recent studies have suggested that inhibitors of SLC6A6 could also serve as anticancer agents. Overexpression of TauT has been associated with the progression of colon and gastric cancer. The pool of known ligands of this transporter is limited and the exact spatial structure of taurine transporter remains unsolved. Understanding its structure could aid in the development of novel inhibitors. Therefore, we utilized homology modelling techniques to create models of TauT. Docking studies and molecular dynamics simulations were conducted to describe protein-ligand interactions. We compared the obtained information for TauT with literature data on other members of the GABA transporter group. Our in silico analysis allowed us to characterize the transporter structure and point out amino acids crucial for ligand binding: Glu406, Gly62 and Tyr138. The significance of selected residues was confirmed through structural studies of mutants. These results will aid in the development of novel taurine transporter inhibitors, which can be explored as anticancer agents.
摘要：
牛磺酸转运蛋白(TauT，SLC6A6）是溶质载体6（SLC6）家族的成员，发挥多种生理作用。SLC6家族分为四个亚家族：GABA（γ-氨基丁酸），单胺,甘氨酸和中性氨基酸转运蛋白。GABA组的蛋白质，包括牛磺酸转运蛋白,主要被认为是治疗中枢神经系统疾病的治疗靶点。然而,最近的研究表明，SLC6A6的抑制剂也可以作为抗癌药物。TauT的过表达与结肠癌和胃癌的进展有关。该转运蛋白的已知配体库有限，牛磺酸转运蛋白的确切空间结构仍未解决。了解其结构有助于开发新型抑制剂。因此,我们利用同源建模技术来创建TauT模型。进行对接研究和分子动力学模拟以描述蛋白质-配体相互作用。我们将获得的TauT信息与GABA转运蛋白组其他成员的文献数据进行了比较。我们的计算机模拟分析使我们能够表征转运蛋白结构，并指出对配体结合至关重要的氨基酸：Glu406，Gly62和Tyr138。通过突变体的结构研究证实了所选残基的重要性。这些结果将有助于开发新型牛磺酸转运蛋白抑制剂，可以作为抗癌剂进行探索。
