Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes
Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes
复制标题
DOI：
10.1073/pnas.0904064106
复制
发表时间：
2009-06-09
影响因子：
11.1
通讯作者：
Mangelsdorf, David J.
中科院分区：
文献类型：
--
作者：
Wang, Zhu;Zhou, X. Edward;Mangelsdorf, David J.
线虫寄生是一个世界性的健康问题，导致超过 10 亿人营养不良和发病。人们对控制感染的分子机制知之甚少。在此，我们报道了一种进化上保守的核激素受体信号通路控制着几种线虫寄生虫（包括粪类圆线虫、钩口线虫属和美洲板线虫）3期感染性幼虫（iL3）的发育。与自由生活的秀丽隐杆线虫一样，类固醇激素样 dafachronic 酸通过激活核受体 DAF-12 的直系同源物，诱导寄生线虫中 dauer 样 iL3 的恢复。此外，给予 dafachronic 酸显着减少了粪圆线虫中的致病性 iL3 种群，表明 DAF-12 配体可用于治疗播散性类圆线虫病。为了了解靶向 DAF-12 的药理学，我们解析了与 dafachronic 酸共结晶的粪圆线虫 DAF-12 配体结合结构域的 3 维结构。这些结果揭示了 DAF-12 配体结合的分子基础，并将核受体确定为寄生线虫的独特治疗靶点。
Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes.