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首页> 外文期刊>The FEBS journal >Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni
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Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni

机译：Schistosoma Mansoni脱氢脱氢酶功能和抑制的结构基础

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Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target-based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone analogue inhibitor 2-((4-fluorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure-guided design of SmDHODH inhibitors.
机译：血吸虫病是一个严重的公共卫生问题，流行于热带和亚热带地区，尤其是在没有安全饮用水和适当卫生设施的贫困社区。78个国家报告了传播，其控制依赖于过去30年中使用的单一药物吡喹酮。我们的工作重点是开发基于靶点的药物发现策略，以开发治疗血吸虫病的新疗法。特别是，我们对评估二氢乳清酸脱氢酶（DHODH）作为药物靶点感兴趣。DHODH是一种黄酶，在从头嘧啶核苷酸生物合成途径的第四个也是唯一一个氧化还原步骤中催化（S）-二氢乳清酸盐（DHO）立体特异性氧化为乳清酸盐。在此之前，我们确定用于治疗疟疾的阿托伐喹酮及其类似物是针对曼氏血吸虫DHODH（SmDHODH）的有效和选择性抑制剂。在本文中，我们报道了SmDHODH与阿托伐醌类似物抑制剂2-（（4-氟苯基）氨基）-3-羟基萘-1,4-二酮（QLA）配合物的第一个晶体结构。我们讨论了三个主要发现：（a）活性位点环的开放构象和2类DHODH的一个新的瞬时药物袋的揭幕；（b） 存在仅存在于血吸虫属DHODHs中的突起结构域，该结构域被发现控制和调节抑制剂结合位点的动力学；（c） atovaquone类似物与SmDHODH的意外绑定模式的详细说明。我们的发现有助于理解2类DHODH的催化机制，并为SmDHODH抑制剂的结构导向设计提供分子基础。

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