This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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