Flavohemoglobins (FHbs) are members of the globin superfamily, widely distributed among prokaryotes and eukaryotes that have been shown to carry out nitric oxide dioxygenase (NOD) activity. In prokaryotes, such as Escherichia coli, NOD activity is a defence mechanism against the NO release by the macrophages of the hosts' immune system during infection. Because of that, FHbs have been studied thoroughly and several drugs have been developed in an effort to fight infectious processes. Nevertheless, the protein's structural determinants involved in the NOD activity are still poorly understood. In this context, the aim of the present work is to unravel the molecular basis of FHbs structural dynamics-to-function relationship using state of the art computer simulation tools. In an effort to fulfill this goal, we studied three key processes that determine NOD activity, namely i) ligand migration into the active site ii) stabilization of the coordinated oxygen and iii) intra-protein electron transfer (ET). Our results allowed us to determine key factors related to all three processes like the presence of a long hydrophobic tunnel for ligand migration, the presence of a water mediated hydrogen bond to stabilize the coordinated oxygen and therefore achieve a high affinity, and the best possible ET paths between the FAD and the heme, where water molecules play an important role. Taken together the presented results close an important gap in our understanding of the wide and diverse globin structural-functional relationships.

译文

黄素血球蛋白(FHbs)是球蛋白超家族的成员,广泛分布于原核生物和真核生物之间,已被证明具有一氧化氮双加氧酶(NOD)活性。在诸如大肠杆菌的原核生物中,NOD活性是抵抗宿主免疫系统巨噬细胞在感染过程中释放NO的防御机制。因此,已经对FHb进行了深入研究,并开发了几种药物来对抗感染过程。然而,仍不清楚对涉及NOD活性的蛋白质的结构决定因素。在这种情况下,本工作的目的是使用最先进的计算机模拟工具来揭示FHbs结构动力学与功能关系的分子基础。为了实现这一目标,我们研究了确定NOD活性的三个关键过程,即i)配体迁移到活性位点ii)配位氧的稳定化和iii)蛋白质内电子转移(ET)。我们的结果使我们能够确定与所有三个过程相关的关键因素,例如存在长的疏水性配体迁移隧道,存在水介导的氢键以稳定配位的氧并因此实现高亲和力以及最佳的ET FAD和血红素之间的通道,其中水分子起着重要作用。综上所述,所提出的结果弥合了我们对广泛而多样的球蛋白结构-功能关系的理解中的一个重要空白。

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