STRUCTURAL MECHANISM OF THE T GONDII UPRT, A TARGET FOR STRUCTURAL-BASED DRUG D

T GONDII UPRT 的结构机制，基于结构的药物 D 的靶标

• 批准号: 7721784
• 负责人: RICHARD GERALD BRENNAN
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721784
• 关键词: Binding; Biochemical; Biological Process; Complex; Computer Retrieval of Information on Scientific Projects Database; Diphosphates; Drug Design; Enzymes; Evaluation; Funding; Future; Grant; Institution; Kinetics; Laboratories; Metabolic Pathway; Nucleic Acids; Nucleotides; Numbers; Parasites; Pharmaceutical Preparations; Phosphoribosyl Pyrophosphate; Proteins; Protozoa; Purines; Pyrimidine; Pyrimidines; Research; Research Personnel; Resolution; Resources; Site; Source; Structure; Toxoplasma gondii; Transcriptional Regulation; United States National Institutes of Health; Uracil; Uracil phosphoribosyltransferase; Uridine Monophosphate; Work; base; interest; mutant; purine; three dimensional structure; ultra high resolution

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. The major research focus of the Brennan Laboratory is to understand the relationship between the 3-D structures of proteins and their biochemical and biological functions. These approaches are being used to study transcription regulation, protein-nucleic acid interaction, multidrug recognition and binding and the mechanisms of purine and pyrimidine salvage in protozoa. Our interest is also directed in structure-based drug design. One protein of interest is the uracil phosphoribosyltransferase (UPRT) from the opportunistic parasitic protozoan, Toxoplasma gondii, which catalyzes the transfer of uracil to D-phosphoribosyl pyrophosphate (PRPP) releasing pyrophosphate and creating the nucleotide monophosphate UMP. The salvaged UMP can then be used in a number of metabolic pathways. This enzyme presents a very good target to exploit in our attempts to discover new drugs against this opportunistic parasite. The substrate recognition and catalytic mechanisms of UPRT must be understood fully. Previous studies from our lab have set the groundwork for the complete structural and mechanistic characterization of UPRT and we are carrying out the next key set of studies. Specifically, we are working on the refinement of the ultra high resolution (1.05 ¿ resolution) structure of apo UPRT and the high resolution structures of a number of key binary and ternary complexes. In parallel, we are carrying out a thorough kinetic evaluation of her wild type protein and a number of site directed mutants. Finally, this information starts to develop the structural parameters that will guide our future drug design attempts.

该副本是使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，这是调查员的机构。 布伦南实验室的主要研究重点是了解蛋白质的3-D结构与其生化和生物学功能之间的关系。这些方法用于研究转录调控，蛋白质核酸的相互作用，多药识别和结合以及原生动物中购买和嘧啶分析的机制。我们的兴趣也针对基于结构的药物设计。一种感兴趣的蛋白是来自机会性寄生虫原生动物毒质剂巨型毒素的尿嘧啶磷酸糖基转移酶（UPRT），它催化了尿嘧啶向D-磷酸蛋白磷酸D-磷酸磷酸（PRPP）释放吡磷酸盐（PRPP）释放吡磷酸酯和产生核磷酸盐和产生核磷酸单磷酸单磷酸单磷酸单磷酸单磷酸单磷酸单球。然后可以在许多代谢途径中使用挽救的UMP。这种酶为我们试图发现这种机会主义寄生虫的新药提供了一个非常好的目标。必须充分理解UPRT的底物识别和催化机制。我们实验室的先前研究为UPRT的完整结构和机械表征奠定了基础，我们正在进行下一组关键研究。具体而言，我们正在研究APO UPRT的超高分辨率（1.05€andosolution）结构以及许多关键二元和三元复合物的高分辨率结构。同时，我们正在对她的野生型蛋白质和许多位置的定向突变体进行彻底的动力学评估。最后，这些信息开始开发结构参数，这些参数将指导我们未来的药物设计尝试。