Probing the Structural Dynamics of the Plasmodium falciparum Tunneling-Fold Enzyme 6-Pyruvoyl Tetrahydropterin Synthase to Reveal Allosteric Drug Targeting Sites.
Probing the Structural Dynamics of the Plasmodium falciparum Tunneling-Fold Enzyme 6-Pyruvoyl Tetrahydropterin Synthase to Reveal Allosteric Drug Targeting Sites.
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DOI：
10.3389/fmolb.2020.575196
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发表时间：
2020
影响因子：
5
通讯作者：
Tastan Bishop Ö
中科院分区：
文献类型：
--
作者：
Khairallah A;Ross CJ;Tastan Bishop Ö
叶酸从头合成途径是许多感染性疾病治疗中公认的药物靶点。抗疟抗叶酸药物已被证明对疟疾有效，然而，在两种主要靶向酶：二氢叶酸还原酶和二氢脲合酶上出现了快速耐药性。需要确定替代抗叶酸药物和新的代谢靶点是迫在眉睫的重要性。6-丙酮四氢蝶呤合成酶（PTPS）酶属于隧道折叠蛋白超家族，其特征是具有明显的中心隧道/空腔。该酶催化寄生虫从头合成叶酸途径的第二反应步骤，并负责将7,8-二氢蝶呤转化为6-丙酮叶-四氢蝶呤。在这项研究中，我们使用各向异性网络模型研究了恶性疟原虫PTPS的结构动力学，以阐明驱动该酶功能的集体运动，并确定其结合特性的变构调节的潜在位点。基于我们的模态分析，我们在n端结构域和中心螺旋中确定了控制活性位点可及性的关键位点。值得注意的是，n端结构域被证明通过一种独特的扭曲运动来调节隧道的开放到封闭的转变，这种扭曲运动使蛋白质的核心变形。我们进一步将动态分析与基序发现相结合，揭示了疟原虫物种所特有的高度保守的基序，这些基序位于n端结构域和中心螺旋。这为药物的有效设计提供了必要的结构信息，如变构调节剂，它们具有高特异性和低毒性，因为它们不靶向人类高度保守的PTPS活性位点。
The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties. Based on our modal analysis, we identified key sites in the N-terminal domains and central helices which control the accessibility to the active site. Notably, the N-terminal domains were shown to regulate the open-to-closed transition of the tunnel, via a distinctive wringing motion that deformed the core of the protein. We, further, combined the dynamic analysis with motif discovery which revealed highly conserved motifs that are unique to the Plasmodium species and are located in the N-terminal domains and central helices. This provides essential structural information for the efficient design of drugs such as allosteric modulators that would have high specificity and low toxicity as they do not target the PTPS active site that is highly conserved in humans.
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