UC Riverside

March 2022 marks two years since the Covid-19 Pandemic began. Two years on, battle with the virus still continues. Officially the number of lives lost to the virus is reported to be around 6 Million but a recent study highlights that this number could be a huge undercount and the true estimate may account to three times that of the reported value. With the virus still circulating worldwide, it holds the opportunity to continue evolving and emerge as a variant capable of evading the human immune response. Therefore new drugs will be needed apart from the approved ones to counter the looming threat of resistance. For doing so, deeper understanding of the mechanistic basis of how the different viral proteins function is needed. In this study, we unravel structural basis of NSP 7-8 complex formation and investigate its dynamic assembly to form an active NSP 7-8-12 core replication complex. Structure-guided mutagenesis, combined with biochemical and enzymatic assays, further reveals a structural coupling between the two oligomer interfaces of NSP 7-8, as well as the importance of these interfaces for the RdRP activity of the NSP7-NSP8-NSP12 complex. In another project, we investigated the pathogen-host interaction based on SARS-CoV-2 Nucleocapsid protein and human G3BP1 protein. This aspect of our study reveals the biochemical and structural basis of the SARS-CoV-2 N1-25-G3BP1NTF2 interaction, revealing a ‘ϕ-x-F’ motif to be the primary and indispensable determinant of the interaction and flanking residues underpins diverse secondary interactions. Mutation of the key interaction residues of the SARS-CoV-2 N1–25 -G3BP1NTF2 complex leads to disruption of the SARS-CoV-2 N- G3BP1 interaction in vitro. In all, our results provide a molecular basis of the strain- specific interaction between SARSCoV-2 N and G3BP1, which has important implications for the development of novel therapeutic strategies against SARS-CoV-2 infection.