HIV frameshift site RNA structure and ligand binding

HIV移码位点RNA结构和配体结合

• 批准号: 7039039
• 负责人: Samuel E Butcher
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039039
• 关键词: X ray crystallography; antiAIDS agent; binding sites; chemical structure function; crosslink; frameshift mutation; gene expression; genetic translation; human immunodeficiency virus 1; human immunodeficiency virus 2; intermolecular interaction; ligands; nuclear magnetic resonance spectroscopy; nucleic acid structure; ribosomes; simian immunodeficiency virus; thermodynamics; virus RNA; virus genetics

DESCRIPTION (provided by applicant): The expression of HIV Pol genes is entirely dependent upon a programmed -1 translational frameshift. Frameshifting is mediated by an RNA element that includes a slippery site and a highly conserved, downstream structure. The downstream RNA structure stimulates frameshifting through an unknown mechansim. The objective is to develop an atomic-level understanding of the structure and function of the frameshift site RNA. Dr. Butcher will determine the NMR structures of the frameshift site RNAs from HIV-1 group M, as well as from HIV-2 and SIV-SMM. These structures are broadly recognized to be attractive targets for the development of new therapeutics. Therefore, as a step towards the rational development of second generation RNA binding ligands with enhanced specificity, the structure of the HIV-1 frameshift site RNA bound to a novel small molecule with anti-HIV activity, guanidino neomycin B will be determined. Finally, in order to more broadly understand the structure and function of the frameshift site RNA, photoreactive RNA modifications will be used to probe its interactions with the translational machinery by laser-induced cross-linking. The resulting data will be mapped to the ribosomal and frameshift site RNA structures to produce the first view of the frameshifting interaction. The specific aims are: 1. Determine the NMR structure of the entire HIV-1 frameshift site (FS) RNA. 2. Investigate the structural and thermodynamic effects of guanidino glycoside binding. 3. Determine the structure of the HIV-2 and SIV-SMM FS RNAs. 4. Identify sites of interaction between the HIV FS RNA and translational machinery.

描述（由申请人提供）：HIV POL基因的表达完全取决于编程的-1翻译移屏。框架介导的RNA元素介导，RNA元件包括一个滑板位点和高度保守的下游结构。下游的RNA结构刺激了未知的机甲的壁画。目的是建立对移状位点RNA的结构和功能的原子水平的理解。 Butcher博士将确定来自HIV-1组的Frameshift位点RNA的NMR结构，以及HIV-2和SIV-SMM。这些结构广泛认为是开发新疗法的有吸引力的靶标。因此，作为具有增强特异性的第二代RNA结合配体的合理发展的一步，HIV-1 Frameshift位点RNA的结构RNA与具有抗HIV活性的新型小分子结合，将确定圭anidino neomycin b。最后，为了更广泛地了解移码位点RNA的结构和功能，将使用光电反应性RNA修饰来探测其与激光诱导的交联的相互作用。所得数据将映射到核糖体和移状位点RNA结构到 产生壁画相互作用的第一视图。 具体目的是： 1。确定整个HIV-1移状位点（FS）RNA的NMR结构。 2。研究鸟翼糖苷结合的结构和热力学作用。 3。确定HIV-2和SIV-SMM FS RNA的结构。 4。确定HIV FS RNA与翻译机械之间相互作用的位点。