STRUCTURE/FUNCTION OF GLUTATHIONE S-TRANSFERASE SYSTEMS

我们的目标是通过以下方式提供详细的结构信息 系统的结晶学研究，对于理解 谷胱甘肽S转移酶的结构与功能关系 提供防止致癌的遗传毒性亲电体的保护。商品及服务税 也被发现与人的寿命和衰老密切相关 雌性小鼠，其中GST水平降低与 随着年龄的增长，对疾病和药物的易感性增加。 也有人认为，GST在 对寄生虫的免疫防御。大鼠、小鼠和狒狒的疫苗接种 GST显著减少了蠕虫的数量 人口。近年来，也有人提出商品及服务税是 对某些肿瘤细胞的抗药性负责。因此这是一门知识 这一家族酶的结构-功能关系可能具有 认识预防相关问题的长远意义 治疗癌症，控制肿瘤，治疗寄生虫病，以及 了解衰老过程中的压力。我们最近发展了一个 Mu级GST分为四种不同的晶型，并已获得晶体 对于四个人类阿尔法级GST，总共形成了八种晶型。 我们现在已经解决了其中五种晶型的结构 分子置换方法。在这份提案中，我们计划完善这些 晶体结构。我们的目标是比较它们的结构，以便 确定底物结合引起的构象变化。我们的目标是 为了定位亲电底物的结合位置，其位置 目前还不得而知。我们计划将这些结构与 不同级别的GST。此外，我们计划将其结晶，并 解决果蝇GSTs的结构，其中一个有序列 与大肠杆菌中严格的饥饿蛋白同源。我们还计划 结晶和研究GSTs的突变结构。建议数 研究可以回答关于该结构的许多关键问题-- GST的功能。它还将增加我们对 大分子识别的分子基础。

Our objective is to provide detailed structural information, through systematic crystallographic investigations, necessary in understanding the structure-function relationship of the glutathione S-transferase provide protection against cancer-causing genotoxic electrophiles. GST is also found to be closely related to the lifespan and aging of the female mouse, where a reduced GST level was implicated to be related to increased susceptibility to disease and drugs occurring with advance age. It has also been suggested that GSTs play a pivotal function in the immuno defense against parasites. Vaccinations of rats, mice and baboons with S. Mansoni GST have resulted in a significant reduction of the worm populations. In recent years it has also been suggested that GST is responsible for drug resistance in some tumore cells. Thus a knowledge of the structure-function relationship of this family of enzymes may have long-term significance in understanding problems related to prevention of cancer, control of tumors, treatment of parasitic diseases, and understanding of stress in the aging process. We have recently grown a mu-class GST into four different crystal forms and have obtained crystals for four humanalpha-class GSTs, making a total of eight crystal forms. W have now solved the structures of five of these crystal forms by molecular replacement methods. In this proposal we plan to refine these crystal structures. We aim to compare their structures in order to identify the conformational changes due to the substrate binding. We aim to locate the binding site for the electrophilic substrates,its location is unknown at the present. We plan to compare the structures among different classes of GSTs. In addition, we plan to crystallize and to solve the structures of Drosophila GSTs, one of which has sequence homology to the stringent starvation protein of E. coli. We also plan to crystallize and study the mutant structures of GSTs. The proposed research could answer many of the key questions about the structure- function of GST. It will also increase our knowledge concerning the molecular basis of macromolecular recognition in general.