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， 以基因组 RNA (gRNA) 的形式包装到病毒体中，我们将从细胞中的事件开始阐明如何进行。 转录起始位点的使用定义了 HIV-1 RNA 5'-前导序列的结构，这反过来又决定了是否 RNA 将二聚化并发挥 gRNA 的作用，或者保持单体形式并发挥信使 RNA 的作用。 研究二聚体 gRNA 如何招募病毒 Gag 蛋白以生成复合物，使 gRNA 组装成核 最后，我们将研究病毒颗粒成熟过程中发生的过程，其中 gRNA 凝结成病毒核糖核蛋白复合物，重新包装在成熟的衣壳内，与 tRNA 引物，并为逆转录做准备，我们提出的研究将提供深入的基础。 了解这些过程，这些过程代表了一些最关键但尚未完全阐明的过程 重要的是，我们现在也准备利用这种理解。 针对 HIV-1 RNA 的新型抑制剂的鉴定、表征和开发 总的来说，我们的研究团队在确定 RNA 复合物方面拥有良好的记录和专业知识。 使用最先进的技术分析大RNA和RNA：蛋白质复合物的结构； 体外、病毒粒子和细胞中的生物化学和生物物理特性； 继续执行细胞中的程序化过程和途径；并应用遗传和病毒学； 识别和表征宿主和病毒辅助因子、探究关键机制细节以及测试小分子的工具 抑制剂。