Identification of key amino acid residues in the hTGR5-nomilin interaction and construction of its binding model.
Identification of key amino acid residues in the hTGR5-nomilin interaction and construction of its binding model.
复制标题
DOI：
10.1371/journal.pone.0179226
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sato R
中科院分区：
文献类型：
--
作者：
Sasaki T;Mita M;Ikari N;Kuboyama A;Hashimoto S;Kaneko T;Ishiguro M;Shimizu M;Inoue J;Sato R
TGR 5是G蛋白偶联受体（GPCR）家族的成员，由胆汁酸激活。由于TGR 5促进能量消耗并改善葡萄糖稳态，因此它被认为是治疗代谢疾病的关键靶标。我们以前表明，nomilin，柑橘类柠檬酸，激活TGR 5，并赋予抗肥胖和抗高血糖作用的小鼠。然而，关于TGR 5-nomilin相互作用的分子结构的信息尚未报道。在本研究中，我们发现人TGR 5（hTGR 5）显示出比小鼠TGR 5（mTGR 5）更高的nomilin反应性。使用小鼠-人嵌合TGR 5，我们还发现三个氨基酸残基（Q77 ECL 1、R80 ECL 1和Y893.29）在hTGR 5-nomilin相互作用中是重要的。基于这些结果，使用计算机对接模拟构建hTGR 5-nomilin结合模型，表明nomilin和hTGR 5之间发生四种亲水性氢键相互作用。hTGR 5-nomilin的结合模式与以前报道的其他TGR 5激动剂的结合模式有很大不同，表明TGR 5根据激动剂的类型形成各种结合模式。我们的研究有助于更好地了解TGR 5的结构，这可能有助于开发和筛选新的TGR 5激动剂。
TGR5, a member of the G protein-coupled receptor (GPCR) family, is activated by bile acids. Because TGR5 promotes energy expenditure and improves glucose homeostasis, it is recognized as a key target in treating metabolic diseases. We previously showed that nomilin, a citrus limonoid, activates TGR5 and confers anti-obesity and anti-hyperglycemic effects in mice. Information on the TGR5–nomilin interaction regarding molecular structure, however, has not been reported. In the present study, we found that human TGR5 (hTGR5) shows higher nomilin responsiveness than does mouse TGR5 (mTGR5). Using mouse–human chimeric TGR5, we also found that three amino acid residues (Q77ECL1, R80ECL1, and Y893.29) are important in the hTGR5–nomilin interaction. Based on these results, an hTGR5–nomilin binding model was constructed using in silico docking simulation, demonstrating that four hydrophilic hydrogen-bonding interactions occur between nomilin and hTGR5. The binding mode of hTGR5–nomilin is vastly different from those of other TGR5 agonists previously reported, suggesting that TGR5 forms various binding patterns depending on the type of agonist. Our study promotes a better understanding of the structure of TGR5, and it may be useful in developing and screening new TGR5 agonists.