ENZYMATIC INVESTIGATION AND STRUCTURE-BASED DRUG DESIGN OF TERMINAL URIDYLYLTRAN

末端尿苷酰基的酶学研究和基于结构的药物设计

• 批准号: 7722140
• 负责人: JASON STAGNO
• 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/7722140
• 关键词: Affinity; Binding; Class; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Drug Delivery Systems; Drug Design; Enzymes; Funding; Grant; Institution; Investigation; Lead; Messenger RNA; Mitochondria; Nucleotides; Pharmaceutical Preparations; Process; Proteins; RNA Editing; Research; Research Personnel; Resources; Source; Structure; Transcript; Transferase; Trypanocidal Agents; Trypanosoma; Trypanosoma brucei brucei; United States National Institutes of Health; Uracil Nucleotides; base; cell growth; improved; inhibitor/antagonist; novel; small molecule; 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. Terminal uridylyl transferases (TUTases) are a class of RNA-editing enzymes capable of uridine nucleotide insertion into mRNA transcripts in a template-independent manner. This process is quite extensive in the mitochondria of trypanosomes and these enzymes therefore serve as drug targets for the development of new trypanocides. Eight out of twelve mitochondrial transcripts must be edited in this fashion in order to encode functional proteins, some of which comprising as much as 50% U-insertions in their fully-edited form. This project involves solving the structure of one such enzyme, TbTUT4, with a novel small-molecule inhibitor bound which has been shown to inhibit nucleotide incorporation activity and cell growth of T. brucei. The structure of this complex will lead to further optimization of this drug by improving its binding affinity. The project will also involve solving the crystal structure of a related enzyme, TbMEAT1, whose crystals are very weakly diffracting, even after attempts at optimization, and require synchrotron radiation for reasonable diffraction.

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。 末端尿液转移酶（Tutase）是一类RNA编辑的酶，能够以尿苷核苷酸插入mRNA转录本以独立的方式插入mRNA转录本。 在锥虫的线粒体中，此过程非常广泛，因此这些酶是开发新锥虫的药物靶标。 必须以这种方式编辑十二个线粒体转录本中的八个，以编码功能蛋白，其中一些蛋白质包括以其完整编辑的形式构成50％的U插入。 该项目涉及解决一种这种酶TBTUT4的结构，该酶具有一种新型的小分子抑制剂结合，该抑制剂已显示可抑制核苷酸的掺入活性和T. brucei的细胞生长。 该复合物的结构将通过改善其结合亲和力进一步优化该药物。 该项目还将涉及求解相关酶TBMeat1的晶体结构，即即使尝试优化后，其晶体也非常弱衍射，并且需要同步辐射以进行合理的衍射。