配基分子与可溶性鸟苷酸环化酶血红素结构域作用的理论研究

发布时间：2018-03-12 21:55

  本文选题：可溶性鸟苷酸环化酶　切入点：血红素辅基　出处：《吉林大学》2010年博士论文　论文类型：学位论文

【摘要】： 可溶性鸟苷酸环化酶(soluble Guanylate Cyclase, sGC)作为NO-cGMP信号转导通路中重要的枢纽蛋白,与体内诸多生理、病理现象如神经信号传导、血管舒张、抗血小板凝集、抗平滑肌增生、中风、糖尿病和癌症等息息相关。气体配基分子一氧化氮(Nitric Oxide,NO)是sGC体内的主要激活因子,开启该酶的活性使GTP转化为第二信使cGMP。 在缺乏sGC晶体结构的情况下,首先,我们通过多序列同源比对方法构建了sGC血红素结合结构域的同源模型,并以分子动力学对模型进行了优化和平衡。然后,我们通过LES分子动力学模拟,比对了sGC血红素结合结构域与原核类似蛋白的气体迁移之关系,从原子层面解释和讨论sGC对氧气的区分机制。最后,我们运用密度泛函理论,进行了不同配基RNO分子与血红素辅基结合的模型研究,借助配位化学和分子轨道理论,解释具有sGC激活性质的RNO类化合物激活sGC的机理和规律,为sGC激活剂的虚拟筛选和sGC激活机制的研究奠定了理论基础。
[Abstract]:Soluble guanylate cyclase Guanylate cyclase (sGCase), as an important pivotal protein in NO-cGMP signal transduction pathway, is associated with many physiological and pathological phenomena such as nerve signal transduction, vasodilation, anti-platelet agglutination, anti-smooth muscle hyperplasia, apoplexy. The gas ligand nitric oxide (no) is the main activator of sGC, which turns on the activity of the enzyme to transform GTP into second messenger cGMP. In the absence of sGC crystal structure, we first constructed the homology model of sGC heme binding domain by multiple sequence homology alignment method, and optimized and balanced the model by molecular dynamics. By means of LES molecular dynamics simulation, we compared the relationship between sGC heme binding domain and the gas transport of prokaryotic similar proteins, and explained and discussed the oxygen differentiation mechanism of sGC at the atomic level. Finally, we used density functional theory (DFT). The binding models of different ligand RNO molecules to heme cogroups were studied. By means of coordination chemistry and molecular orbital theory, the mechanism and regularity of sGC activation by RNO compounds with sGC activation properties were explained. It lays a theoretical foundation for the virtual screening of sGC activators and the study of sGC activation mechanism.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R341

【引证文献】

相关博士学位论文 前1条

1 余淑娴;金属镍、锡络合物催化烯烃活化及聚合反应机理研究[D];南昌大学;2014年

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