STRUCTURAL STUDIES OF THERAPEUTIC DRUG TARGETS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 提出了一系列人类和细菌蛋白质的结晶学研究，其统一的主题是每种蛋白质在人类疾病中都发挥着作用。首先，将结合使用MAD和SAD方法来研究假单胞菌蛋白PilY1的结构。这种蛋白是将传染性假单胞菌附着在肺上皮细胞上的粘附物，导致囊性纤维化患者的致命性定植。其次，人类药物代谢蛋白羧酸酯酶1(HCE1)的晶体结构将在与神经毒剂(如沙林、梭曼)和神经毒剂类似物的络合物中确定。第三，将确定人类核受体的晶体结构。例如，核异源受体PXR的结构将在与各种药物和拮抗剂的复合体中确定；PXR是人类的中枢药物受体，控制着主要药物代谢途径在肝脏和其他组织中的表达。在hCE1和核受体的情况下，需要同步辐射，因为我们要与之发生衍射的晶体

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Crystallographic studies of a series of human and bacterial proteins are proposed, with the unifying theme that each protein plays a role in human disease. First, the structure of the Pseudomonas protein PilY1 will be pursued using a combination of MAD and SAD methodologies. This protein is the adhesion that attaches the infectious Psuedomonas bacterium to the lung epithelia, leading to lethal colonizations in patients with cystic fibrosis (CF). Second, crystal structures of the human drug metabolism protein carboxylesterase 1 (hCE1) will be determined in complexes with nerve agents (e.g., sarin, soman) and nerve agent analogues. Third, crystal structures of human nuclear receptors will be determined. For example, structures of the nuclear xenobiotic receptor PXR will be determined in complexes with various drugs and antagonists; PXR is the central drug receptor in humans and controls the expression of the primary drug metabolism pathways in liver and other tissues. In the cases of hCE1 and nuclear receptors, synchrotron radiation is required because the crystals we have diffract to