Center for Structural Biology of HIV RNA

HIV RNA结构生物学中心

• 批准号: 10505793
• 负责人: ALICE TELESNITSKY
• 金额: $ 91.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-09 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505793
• 关键词: Behavior; Biochemical; Budgets; Capsid; Cells; Chemistry; Complex; Cone; Cryoelectron Microscopy; Crystallography; Development; Engineering; Enzymes; Event; Fullerenes; Genes; Genetic; Genetic Transcription; Goals; HIV; HIV-1; Human Resources; In Vitro; Integration Host Factors; Lead; Learning; Length; Location; Magnetic Resonance Imaging; Mediating; Messenger RNA; Molecular; Morphogenesis; Pathway interactions; Poly A; Process; Proviruses; RNA; RNA Polymerase II; RNA Splicing; Research Personnel; Reverse Transcription; Ribonucleoproteins; Role; Structure; Techniques; Testing; Transcript; Transcription Initiation Site; Transfer RNA; Translations; Viral; Viral Physiology; Virion; Virus; biophysical properties; dimer; gag Gene Products; genomic RNA; inhibitor; novel; particle; pol Gene Products; protein complex; recruit; scaffold; small molecule inhibitor; structural biology; tool; trafficking

Summary/Abstract In this Project, we will analyze the structures and molecular transformations of the HIV-1 RNA molecules that become packaged into virions as genomic RNA (gRNA). Beginning with events in the cell, we will elucidate how transcription start site usage defines the structure of the HIV-1 RNA 5’-leader, which, in turn, dictates whether the RNA will dimerize and function as gRNA or remain monomeric and function as messenger RNA. We will study how the dimeric gRNA recruits the viral Gag protein to generate a complex that nucleates assembly of the immature virion. Finally, we will look at processes that occur during virion maturation, in which the gRNA condenses into a viral ribonucleoprotein complex, is re-packaged inside the mature capsid, anneals with the tRNA primer, and prepares for reverse transcription. Our proposed studies will provide deep fundamental understanding of these processes, which represent some of the most critical but incompletely elucidated molecular mechanisms in HIV-1 replication. Importantly, we are now also poised to exploit this understanding towards the identification, characterization and development of novel inhibitors targeted against HIV-1 RNA and RNA complexes. Collectively, our team of investigators have a strong track record and expertise in determining structures of large RNAs and RNA:protein complexes using state-of-the-art techniques; in analyzing their biochemical and biophysical properties in vitro, in virions, and in cells; in visualizing the complexes as they proceed through their programmed processes and pathways in the cell; and in applying genetic and virological tools to identify and characterize host and viral co-factors, probe key mechanistic details, and test small molecule inhibitors.

摘要/摘要 在这个项目中，我们将分析HIV-1 RNA分子的结构和分子转化。 从单元格中的事件开始，我们将阐明 转录启动站点的使用定义了HIV-1 RNA 5'-LEADER的结构，这反过来又决定了是否是否决定 RNA将二聚并起作用为GRNA或保持单体并作为Messenger RNA起作用。我们将 研究二聚体GRNA如何募集病毒GAG蛋白以产生一种复合物，该复合物是核装配的 未成熟的病毒粒子。最后，我们将研究病毒率成熟过程中发生的过程，其中grna 将冷凝剂冷凝为病毒核糖核蛋白复合物，在成熟的衣壳内重新包装，并将其退火与 tRNA底漆，并准备逆转录。我们提出的研究将提供深厚的基本 对这些过程的理解，这些过程代表了一些最关键但未完全阐明的过程 HIV-1复制中的分子机制。重要的是，我们现在也被中毒以利用这种理解 针对针对HIV-1 RNA和的新型抑制剂的鉴定，表征和发展 RNA复合物。总的来说，我们的调查人员团队在确定方面具有很强的往绩和专业知识 大型RNA和RNA的结构：使用最新技术的蛋白质复合物；在分析他们的过程中 体外，病毒体和细胞中的生化和生物物理特性；在可视化络合物时 通过其在细胞中的编程过程和途径进行操作；并应用遗传和病毒学 识别和表征宿主和病毒共同因素，探测关键机理细节并测试小分子的工具 抑制剂。