X-ray structures of Na-GST-1 and Na-GST-2 two glutathione s-transferase from the human hookworm Necator americanus
X-ray structures of Na-GST-1 and Na-GST-2 two glutathione s-transferase from the human hookworm Necator americanus
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DOI：
10.1186/1472-6807-7-42
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发表时间：
2007-06-26
影响因子：
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通讯作者：
Hotez, Peter J.
中科院分区：
文献类型：
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作者：
Asojo, Oluwatoyin A.;Homma, Kohei;Hotez, Peter J.
背景：人类钩虫感染是发展中国家成人和儿童贫血和营养不良的主要原因。作为控制钩虫感染的持续努力的一部分，人类钩虫疫苗倡议已经从寄生虫的感染性L3幼虫阶段和成虫阶段确定了候选疫苗抗原。成体阶段抗原包括胞质谷胱甘肽-S-转移酶（GST）。线虫GST通过还原型谷胱甘肽的亲核加成促进多种亲电底物（药物）的失活和降解。结果：在2.4埃和1.9埃的分辨率范围内分别解析了美洲钩虫（Necatoramericanus）的两种主要GST-Na-GST-1和Na-GST-2的晶体结构。Na-GST-1的结构被精细化为R因子18.9%（无R 28.3%），而Na-GST-2的结构被精细化为R因子17.1%（无R 21.7%）。在发酵过程中取代的谷胱甘肽结合在NaGST-2的每个单体的谷胱甘肽结合位点（G-位点）。Na-GST-1是未复合的，其G位点被Gln 50废除。结论：Na-GST-1和Na-GST-2的三维结构显示了人钩虫GST的两种结构。虽然Na-GST-2的GST-复合物结构揭示了Na-GST-1的典型GST G-位点，但这表明为了结合底物GST需要一定的构象柔性。此外，两者的整体结合腔更大，更开放，以及更容易获得不同的配体比那些具有其他主要解毒机制的生物体的GST。这项研究的结果可以帮助设计新的药物和疫苗抗原。
Background: Human hookworm infection is a major cause of anemia and malnutrition of adults and children in the developing world. As part of on-going efforts to control hookworm infection, The Human Hookworm Vaccine Initiative has identified candidate vaccine antigens from the infective L3 larval stages and adult stages of the parasite. Adult stage antigens include the cytosolic glutathione-S-transferases (GSTs). Nematode GSTs facilitate the inactivation and degradation of a variety of electrophilic substrates (drugs) via the nucleophilic addition of reduced glutathione. Parasite GSTs also play significant roles in multi-drug resistance and the modulation of host-immune defense mechanisms.Results: The crystal structures of Na-GST-1 and Na-GST-2, two major GSTs from Necator americanus the main human hookworm parasite, have been solved at the resolution limits of 2.4 angstrom and 1.9 angstrom respectively. The structure of Na-GST-1 was refined to R-factor 18.9% (R-free 28.3%) while that of Na-GST-2 was refined to R-factor 17.1% (R-free 21.7%). Glutathione usurped during the fermentation process in bound in the glutathione binding site (G-site) of each monomer of NaGST-2. Na-GST-1 is uncomplexed and its G-site is abrogated by Gln 50. These first structures of human hookworm parasite GSTs could aid the design of novel hookworm drugs.Conclusion: The 3-dimensional structures of Na-GST-1 and Na-GST-2 show two views of human hookworm GSTs. While the GST-complex structure of Na-GST-2 reveals a typical GST G-site that of Na-GST-1 suggests that there is some conformational flexibility required in order to bind the substrate GST. In addition, the overall binding cavities for both are larger, more open, as well as more accessible to diverse ligands than those of GSTs from organisms that have other major detoxifying mechanisms. The results from this study could aid in the design of novel drugs and vaccine antigens.