Liu Xin, Kai Ming, Jin Lian, Wang Rui
Institute of Biochemistry and Molecular Biology, School of Basic Medical Science, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China.
J Comput Aided Mol Des. 2009 Jun;23(6):321-32. doi: 10.1007/s10822-009-9262-7. Epub 2009 Feb 13.
A growing body of evidence indicated that the G protein coupled receptors exist as homo- or hetero-dimers in the living cell. The heterodimerization between mu and delta opioid receptors has attracted researchers' particular interests, it is reported to display novel pharmacological and signalling regulation properties. In this study, we construct the full-length 3D-model of mu and delta opioid receptors using the homology modelling method. Threading program was used to predict the possible templates for the N- and C-terminus domains. Then, a 30 ns molecular dynamics simulations was performed with each receptor embedded in an explicit membrane-water environment to refine and explore the conformational space. Based on the structures extracted from the molecular dynamics, the likely interface of mu-delta heterodimer was investigated through the analysis of protein-protein docking, cluster, shape complementary and interaction energy. The computational modelling works revealed that the most likely interface of heterodimer was formed between the transmembrane1,7 (TM1,7) domains of mu receptor and the TM(4,5) domains of delta receptor, with emphasis on mu-TM1 and delta-TM4, the next likely interface was mu(TM6,7)-delta(TM4,5), with emphasis on mu-TM6 and delta-TM4. Our results were consistent with previous reports.
越来越多的证据表明，G蛋白偶联受体在活细胞中以同二聚体或异二聚体形式存在。μ和δ阿片受体之间的异二聚化引起了研究人员的特别关注，据报道其具有新的药理学和信号调节特性。在本研究中，我们使用同源建模方法构建了μ和δ阿片受体的全长三维模型。使用穿线程序预测N端和C端结构域的可能模板。然后，对每个嵌入明确膜水环境中的受体进行30纳秒的分子动力学模拟，以优化和探索构象空间。基于从分子动力学中提取的结构，通过蛋白质-蛋白质对接、聚类、形状互补和相互作用能分析研究了μ-δ异二聚体的可能界面。计算建模工作表明，异二聚体最可能的界面形成于μ受体的跨膜1、7（TM1,7）结构域和δ受体的TM（4,5）结构域之间，重点是μ-TM1和δ-TM4，下一个可能的界面是μ（TM6,7）-δ（TM4,5），重点是μ-TM6和δ-TM4。我们的结果与先前的报道一致。
