CHARACTERIZING THE CONFORMATIONAL CHANGE OF INFLUENZA HEMAGGLUTININ BY SAXS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 流感病毒仍然是对全球健康的严重威胁。 血凝素（HA）是在感染人类的所有流感病毒中发现的主要表面蛋白。 尽管广泛的结构和生物化学研究揭示了HA的构象变化的程度，转变途径和动力学仍然是未知的，主要是由于缺乏有效的工具来研究这种动态和大规模的转变。 在这个项目中，一个领先的专家团队在时间分辨SAXS/WAXS研究，结构模拟，结构和功能的HA研究，已组装到表征HA的转变。 具体目标是：（1）。HA构象转变的时间分辨SAXS/WAXS研究，有望在真实的时间内捕获不同的转变中间体。 （二）、HA过渡中间体分子包膜的重建。 （三）、通过SAXS/WAXS捕获的过渡中间体，使用TMD模拟生成HA构象转变的高分辨率图库。 从这种创新性研究中获得的新知识有望为流感病毒进入宿主细胞的分子机制提供关键的新见解，指导新实验的设计以进行更好的机制和结构研究，并最终有利于开发阻断或限制流感病毒进入宿主细胞的药物。

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. Influenza virus remains a serious threat to global health. Hemagglutinin (HA) is a major surface protein found in all influenza viruses that infect humans. Despite the extensive structural and biochemical studies of HA that revealed the extent of the conformational change, the transition pathway and kinetics remain mostly unknown, largely due to the lack of effective tools to study such a dynamic and large-scale transition. In this project, a team of leading experts in time-resolved SAXS/WAXS study, structure simulation, and structural and functional study of HA, has been assembled to characterize the transition of HA. The Specific Aims are: (1). Time-resolved SAXS/WAXS study of the conformational transition of HA that is expected to capture distinct transition intermediates in real time. (2). Reconstruction of molecular envelopes of the transition intermediates of HA. (3). Generation of a high-resolution gallery of the conformational transition of HA using TMD simulations guided by SAXS/WAXS-captured transition intermediates. The new knowledge derived from such an innovative study is expected to provide critical new insights into the molecular mechanism of influenza entry into host cells, to guide design of new experiments for better mechanistic and structural studies, and ultimately, to benefit the development of drugs that block or limit the entry of influenza virus into host cells.