Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-1
Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-1
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DOI：
10.1039/c5ra26102c
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发表时间：
2016-02
期刊：
影响因子：
3.9
通讯作者：
Juan Zhang;Shikai Gu;Xianqiang Sun;Weihua Li;Yun Tang;Guixia Liu
中科院分区：
文献类型：
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作者：
Juan Zhang;Shikai Gu;Xianqiang Sun;Weihua Li;Yun Tang;Guixia Liu
胰高血糖素样肽-1 受体 (GLP-1R) 因其对 2 型糖尿病 (T2DM) 的巨大治疗作用而引起了研究人员的关注。然而，由于GLP-1R的全长晶体结构尚未被揭示，其分子结合模式和激活机制仍不清楚，这将成为发现新型强效GLP-1R激动剂的障碍。在本研究中，我们构建了GLP-1R的全长模型，并通过同源建模、蛋白质-蛋白质对接和分子动力学模拟等一系列计算方法探索了GLP-1和GLP-1R之间的结合模式。我们的模型与之前的实验一致，MD 模拟结果验证了 GLP-1 和 GLP-1R 之间的结合模式是合理的。更重要的是，我们发现GLP-1的缺失或存在显着影响GLP-1R胞外结构域（ECD）的构象。 apo形式的GLP-1R稳定在“封闭”状态，不利于GLP-1的结合，类似于GCGR。相比之下，在 GLP-1/GLP-1R 复合物中，GLP-1R 保持“开放”状态。
The glucagon-like peptide-1 receptor (GLP-1R) has captivated researchers because of its tremendous therapeutic effects for the treatment of type 2 diabetes mellitus (T2DM). However, since the full-length crystal structure of GLP-1R has not been revealed yet, the molecular binding mode and the activation mechanism remain unclear, which will be the obstacle for the discovery of novel potent GLP-1R agonists. In the present study, we constructed the model of GLP-1R in its full length and explored the binding modes between GLP-1 and GLP-1R by means of a bunch of computational methods including homology modeling, protein–protein docking, and molecular dynamics simulations. Our model is in agreement with previous experiment and the results from our MD simulations that verified the binding modes between GLP-1 and GLP-1R are reasonable. What's more, we found the absence or presence of GLP-1 significantly affected the conformation of extracellular domain (ECD) of GLP-1R. The GLP-1R in the apo form stabilized in a ‘closed’ state which is unfavorable to the binding of GLP-1, resembling as the GCGR. By contrast, in the GLP-1/GLP-1R complex, GLP-1R maintained an ‘open’ state.