RAPID: Structural investigation of interactors of SARS CoV 2

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The SARS-COV-2 virus genome encodes a very small set of proteins. Having such a minimal genome means that the virus relies on host factors to complete its infectious cycle. Researchers supported by this award will investigate the mechanisms by which interactions between viral and host cell proteins might antagonize innate immune defenses and lead to increased virulence. Elucidating the structural basis for how SARS-COV-2 hijacks and disrupts host cellular processes may aid in the development of host-directed therapies as a means to combat epidemics and will provide new insight into how genetic variation of host proteins can influences differences in infection severity and spread between populations and species. Data and resources from these studies will be rapidly disseminated through public WWW-sites, social media, shared data repositories, and published in peer-reviewed scientific journals.Protein regions that are structurally dynamic upon changing the data collection temperature are highly correlated with small molecule binding sites. Studies supported by this award will test the hypothesis that the regions of viral and host proteins that are most structurally susceptible to temperature perturbation, detectable by multi-temperature synchrotron and x-ray free electron laser (XFEL) experiments, are likely to represent the footprints of protein-protein interactions and to bind small molecule ligands. The researchers will use an innovative combination of multi-temperature X-ray data collection of individual proteins at synchrotrons and XFELs, high throughput crystal fragment screening, and structure determination of viral-human complexes. Results from these studies will advance the understanding of SARS-COV-2 biology and may also yield more generalizable insights into mechanisms of virulence. This RAPID award to the University of California-San Francisco is made by the Division of Biological Infrastructure using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.