Functional and structural insights revealed by molecular dynamics simulations of an essential RNA editing ligase in Trypanosoma brucei.
Functional and structural insights revealed by molecular dynamics simulations of an essential RNA editing ligase in Trypanosoma brucei.
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DOI：
10.1371/journal.pntd.0000068
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发表时间：
2007-11-14
影响因子：
3.8
通讯作者：
McCammon JA
中科院分区：
文献类型：
--
作者：
Amaro RE;Swift RV;McCammon JA
RNA编辑连接酶1（Tbs1）是布氏锥虫昆虫和血液形式生存所必需的，布氏锥虫是造成毁灭性热带疾病非洲昏睡病的寄生虫。TbR1参与的RNA编辑类型是锥虫所特有的，并且已知不存在与人类相似的同源物。此外，高分辨率的晶体结构揭示了活性位点的几个独特特征，使这种酶成为基于结构的药物设计的一个有前途的靶标。在这项工作中，两个20 ns的原子分子动力学（MD）模拟研究Tbatomic 1的动力学，有和没有ATP底物存在。活性位点的灵活性，保守的残基和结晶水分子的动力学，以及Tb1和ATP底物之间的相互作用的Tb1的功能的上下文中进行了研究和讨论。ATP结合后的局部和全局运动的差异表明，两个外周环，独特的锥虫，可能参与域间信号事件。值得注意的是，在apo模拟过程中发生了酶活性位点的显著结构重排，在ATP结合位点附近打开了一个额外的空腔，该空腔可以用于开发针对这种原生动物寄生虫的有效抑制剂。最后，在MD模拟的合奏平均静电计算揭示了一个新的推定RNA结合位点，一个发现，以前一直逃避科学家。最终，我们利用通过MD模拟获得的见解来做出一些预测和建议，我们预计这将有助于指导未来针对这种重要酶的实验研究和基于结构的药物发现工作。RNA编辑连接酶1（Tbs1）是布氏锥虫昆虫和血液形式生存所必需的，布氏锥虫是造成毁灭性热带疾病非洲昏睡病的寄生虫。TbR1参与的RNA编辑类型是锥虫所特有的，并且已知不存在与人类相似的同源物。在这里，我们使用分子动力学模拟研究TbR 1的动力学，有和没有ATP底物存在。活性位点的灵活性，保守残基和结晶水分子的动力学，以及TbR 1和ATP底物之间的相互作用进行了研究和讨论。在载脂蛋白模拟过程中，酶活性位点的显著结构重排在ATP结合位点附近打开了一个额外的空腔，该空腔可用于开发针对这种原生动物寄生虫的有效抑制剂。最先进的静电学计算揭示了一个新的假定RNA结合位点，这是一个科学家以前没有发现的发现。最终，我们使用通过MD模拟获得的见解进行了几次预测，我们预计这将有助于指导未来的实验研究和基于结构的药物发现工作。
RNA editing ligase 1 (TbREL1) is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high-resolution crystal structure revealed several unique features of the active site, making this enzyme a promising target for structure-based drug design. In this work, two 20 ns atomistic molecular dynamics (MD) simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed in the context of TbREL1's function. Differences in local and global motion upon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme's active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD simulations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions and recommendations, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme. RNA editing ligase 1 (TbREL1) is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. Here we use molecular dynamics simulations to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed. During the apo simulations, a significant structural rearrangement of the enzyme's active site opens an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors against this protozoan parasite. State-of-the-art electrostatics calculations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme.
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