G蛋白偶联受体34同源建模及其与lysoPS类似物对接研究

Homology modeling of G-protein-coupled receptor 34 and docking simulation of the analogs of LysoPS

G蛋白偶联受体34(GPR34)在肥大细胞、肿瘤组织和人体免疫器官中高度选择性表达,但因属于膜蛋白,其三维结构难以测定,不能从分子水平上分析其与药物作用情况。本文选用PDB数据库中与GPR34一级序列同源性最高的4NTJ为模版蛋白进行同源建模,运用拉氏图和Profile-3D进行评估,通过加膜限制和loop区能量优化等方法最终得到合理并且可信度高的3D结构模型。最优模型Verify Score为124.97(期望Verify Score值区间为69.071 1~153.491),预测分析得到14个可能的活性位点。通过最陡下降法和共轭梯度法构建GPR34激动剂分子的最低能量结构,将激动剂分子与预测的蛋白3D结构模型上的活性位点进行分子模拟对接,根据对接模型比较不同激动剂分子与不同蛋白活性位点的相互作用。实验结果对设计GPR34激动剂分子和进一步研究GPR34的结构和功能具有理论指导意义。

The G-protein-coupled receptor 34(GPR34)has been found to be highly selectively expressed in mast cells,tumor tissues,and human immune organs.However,since it is a membrane protein with an unknown three-dimensional structure,the interaction between GPR34 and agonist molecules is not viable for analysis at the molecular level.Based on the known first-order sequence of GPR34,the three-dimensional structure of the GPR34 protein was constructed using the homology modeling method.Moreover,this model was evaluated through the Ramachandran plot and profile-3 D,as well as optimized with molecular dynamics,membrane,and loop methods.As a result,the optimal model for the protein was obtained.The Verify Score model was 130.27,and the expected value range of Verify Score was 60.811 2~135.136.Additionally,14 potential active sites were calculated and evaluated.Simultaneously,the small-molecule agonist of GPR34 was constructed,and the lowest energy conformation of the drug molecule was obtained using the steepest descent method and conjugate gradient method.The agonists were butted to the protein’s active site through the docking method.Also,the models of their actions were generated.In this study,the docking method was used to dock the agonists to the active sites of proteins.Subsequently,the models of their actions was acquired to compare and investigate the interaction between the agonists and the active sites.Finally,this study had theoretical significance for the design of the GPR34 agonist and future clinical trials.