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

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 提出了一系列人类和细菌蛋白的晶体学研究，其统一主题是每种蛋白质在人类疾病中起作用。 首先，将使用疯狂和悲伤的方法组合来追求假单胞菌蛋白py1的结构。 该蛋白是连接感染性的sudeDomonas细菌与肺上皮菌相连的粘附，从而导致囊性纤维化患者（CF）的致命定殖。 其次，将在与神经剂（例如Sarin，Soman）和神经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，将确定人核受体的晶体结构。 例如，将在各种药物和拮抗剂的复合物中确定核异种受体PXR的结构。 PXR是人类中的中央药物受体，并控制肝脏和其他组织中原发性药物代谢途径的表达。在HCE1和核受体的情况下，需要同步辐射，因为晶体我们具有衍射到