Core 1 - Structural Biology Core

摘要-核心1-结构生物学核心 全世界约有4000万人感染艾滋病毒/艾滋病；然而，保护性疫苗或有效的 尽管进行了40年的紧张研究，但治愈方法仍然难以捉摸。HIV-1通过其自身的功能逃避免疫系统 在感染和复制过程中结构的快速演变。杜克大学艾滋病毒结构生物学中心将致力于 HIV-1包膜蛋白进化的结构研究以阐明结构-功能机制 用于病毒进入、B细胞和T细胞的激活，以及抗逆转录病毒治疗后病毒的反弹。结构性的 生物核心(核心1)将通过建立最先进的管道来支持中心的总体任务 使用广泛的实验技术对HIV-1env结构进行分析。核心将提供访问 结构确定的尖端技术，并具有强大的技术开发组成部分 这最终将促进我们对环境的机械性理解。研究项目将受益于 获得用于确定结构的既定方案以及由该技术产生的新方法 以发展为核心的努力。结构生物学核心的具体目标是：1)建立一个高质量的 用于常规表征可溶HIV-1三聚体结构和动力学的吞吐量管道 解析单粒子冷冻-EM；2)开发用于天然HIV-1结构分析的高级工作流程 使用近原子分辨率的冷冻电子断层扫描(ET)原位成像的样品；以及3)建立 HIV-1环境蛋白微秒分辨结构研究的结构方法完成三项工作 拟议的AIMS将提供结构生物学方面的坚实基础设施，以支持 中心及其组件。通过提供对最先进技术的访问来确定结构 以尽可能高的空间和时间分辨率显示HIV-1病毒，将为可视化提供独特的机会 关键的中间体，可以帮助我们了解HIV病毒感染。 确定可溶或天然形式的环境病毒的高分辨率结构的能力将是改善我们的 对艾滋病毒的了解。作为结构生物学核心的一部分开发的技术将产生影响 这项研究超越了艾滋病毒领域，并将有助于其他生物系统的结构研究。通过制造我们的工具 对于结构生物界来说，核心的活动将产生更广泛的影响。

Abstract – Core 1 – Structural Biology Core Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The Duke Center for HIV Structural Biology will pursue structural studies of the evolution of the HIV-1 Envelope (Env) protein to elucidate structure-function mechanisms for viral entry, B-cell and T-cell activation, and viral rebound after antiretroviral therapy ART. The Structural Biology Core (Core 1) will support the overall mission of the Center by establishing a state-of-the-art pipeline for structural analysis of HIV-1 Env using a wide range of experimental techniques. The Core will provide access to cutting-edge techniques for structure determination and have a strong component of technology development that will ultimately advance our mechanistic understanding of Env. The research projects will benefit from having access to established protocols for structure determination as well as new methods resulting from the technology development efforts of the core. The Specific Aims of the Structural Biology Core are 1) to establish a high- throughput pipeline for routine characterization of the structure and dynamics of soluble HIV-1 trimers using high- resolution single-particle cryo-EM; 2) to develop advanced workflows for structural analysis of native HIV-1 samples imaged in-situ using cryo-electron tomography (ET) at near-atomic resolution; and 3) to establish structural methods for microsecond time resolution structural studies of HIV-1 Env. Completion of the three proposed aims will provide a solid infrastructure in structural biology needed to support the overall goals of the Center and its components. By providing access to state-of-the-art technology for the determination of structures of HIV-1 at the highest possible spatial and temporal resolution, will provide unique opportunities for visualizing key intermediates that could inform our understanding of HIV viral infection. The ability to determine high-resolution structures of soluble or native forms of Env will be critical to improve our understanding of HIV. The technologies developed as part of the Structural Biology Core will have implications beyond the field of HIV and would benefit structural studies of other biological systems. By making our tools available to the structural biology community, the activities of the core will have an even wider impact.