STRUCTURAL STUDIES OF THERAPEUTIC DRUG TARGETS

治疗药物靶点的结构研究

• 批准号: 7954336
• 负责人: Matthew R Redinbo
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954336
• 关键词: Adhesions; Bacteria; Bacterial Proteins; Carboxylic Ester Hydrolases; Complex; Computer Retrieval of Information on Scientific Projects Database; Drug Delivery Systems; Drug Receptors; Epithelium; Funding; Grant; Human; Institution; Liver; Lung; Methodology; Nuclear Receptors; Nuclear Structure; Pathway interactions; Pharmaceutical Preparations; Play; Proteins; Pseudomonas; Research; Research Personnel; Resources; Role; Sarin; Series; Soman; Source; Structure; Therapeutic Studies; Tissues; United States National Institutes of Health; Xenobiotics; analog; carboxylesterase; cystic fibrosis patients; drug metabolism; human disease; nerve agent; pregnane X receptor; structural biology; synchrotron radiation

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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 提出了一系列人类和细菌蛋白质的晶体学研究，其统一主题是每种蛋白质在人类疾病中发挥作用。 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。 这种蛋白质是将传染性假单胞菌附着在肺上皮细胞上的粘附剂，导致囊性纤维化 (CF) 患者致命的定植。 其次，将在与神经毒剂（例如沙林、索曼）和神经毒剂类似物的复合物中确定人类药物代谢蛋白羧酸酯酶 1 (hCE1) 的晶体结构。 第三，将确定人类核受体的晶体结构。 例如，核异生物质受体PXR的结构将在与各种药物和拮抗剂的复合物中确定； PXR是人体的中心药物受体，控制肝脏和其他组织中主要药物代谢途径的表达。对于 hCE1 和核受体，需要同步加速器辐射，因为我们衍射的晶体