STRUCTURAL STUDIES OF AIDS-RELATED ENZYMES AND OTHER PATHOGENIC TARGETS

艾滋病相关酶和其他致病靶标的结构研究

• 批准号: 8362410
• 负责人: Vivian Cody
• 金额: $ 0.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362410
• 关键词: Acquired Immunodeficiency Syndrome; Area; Biological; Complex; Data; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Dihydropteroate Synthase; Dimerization; Drug resistance; Enzymes; Escherichia coli; Funding; Goals; Grant; Human; Immunocompromised Host; Investigation; Medical Research; Minnesota; Mutation; Nanotubes; National Center for Research Resources; Opportunistic Infections; Patients; Pneumocystis; Pneumocystis carinii Pneumonia; Principal Investigator; Radiation; Request for Proposals; Research; Research Infrastructure; Research Institute; Resolution; Resources; Role; Site; Site-Directed Mutagenesis; Source; Structure; Therapeutic Agents; Time; United States National Institutes of Health; Variant; cost; design; dimer; inhibitor/antagonist; mortality; novel; pathogen; programs; structural biology; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Cody lab at the Hauptman-Woodward Medical Research Institute (HWI) has a multi-faceted research program that focuses on understanding the role of site specific residues in the design of selective inhibitors of pathogens such as Pneumocystis (Pc), a major cause of opportunistic infection and mortality in immunocompromised patients, particularly those with AIDS. Pneumocystis jirovecii (pj) is the causative agent of Pneumocystis pneumonia (PcP), one of the most frequent and severe opportunistic infections in immunocompromised patients. In this proposal, we request beamtime to develop complementary areas of biological structural research. Recent studies show that mutations accumulate over time in the target enzymes, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) from Pneumocystis, potentially giving rise to drug resistance. A major goal of this project is to characterize pjDHFR and pjDHPS and their variants in order to design effective inhibitors that have potential as therapeutic agents for the treatment of PcP. Site-directed mutagenesis studies on DHFR enzymes are under investigation to determine the role of specific residues in modulating DHFR inhibitor potency and in conferring drug-resistance to pjDHFR as observed in AIDS patient isolates. Structures of human DHFR inhibitor complexes are under investigation to compare their structures with those of the Pneumocystis DHFR enzymes. We require the use of synchrotron radiation to determine high-resolution details of these inhibitor complexes. In another collaborative study (Wagner, Univ. Minnesota), E. coli DHFR dimerization complexes are being investigated to design novel nanotube assemblies. Structural data are needed to validate dimerization assembly and to determine how mutations at the dimer interface modulate nanotube assembly. Sychrotron time is needed as these crystals tend to be small and diffract modestly.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 Hauptman-Woodward医学研究所（HWI）的Cody Lab具有多方面的研究计划，重点是理解特定于病原体的选择性抑制剂在肺炎肺结构（PC）（PC）的选择性抑制剂中的作用，例如肺炎药物（PC），这是免疫症状患者的机会性感染和死亡率的主要原因，尤其是辅助患者。肺囊藻（PJ）是肺炎肺炎肺炎（PCP）的病因，这是免疫功能低下患者中最常见和严重的机会性感染之一。在此提案中，我们要求Beamtime开发生物结构研究的互补领域。最近的研究表明，突变会随着时间的流逝积累在靶酶，二氢叶酸还原酶（DHFR）和二氢蛋白酶合成酶（DHPS）（DHPS）中，可能会引起耐药性。该项目的主要目的是表征PJDHFR和PJDHP及其变体，以设计具有治疗PCP治疗剂潜力的有效抑制剂。正在研究对DHFR酶的位置定向诱变研究，以确定特定残基在调节DHFR抑制剂效力中的作用，并在AIDS患者分离株中观察到的PJDHFR赋予PJDHFR。人类DHFR抑制剂复合物的结构正在研究中，以将其结构与肺炎藻DHFR酶的结构进行比较。我们需要使用同步加速器辐射来确定这些抑制剂复合物的高分辨率细节。在另一项合作研究（明尼苏达州瓦格纳（Wagner，Univ。Wagner））中，正在研究大肠杆菌DHFR二聚体复合物以设计新型的纳米管组件。需要结构数据来验证二聚化组装并确定二聚体界面处的突变如何调节纳米管组件。由于这些晶体往往较小且衍射适中，因此需要Sychrotron Time。