Abstract
The SARS-CoV-2 is the cause of the ongoing Coronavirus disease 19 (COVID-19) pandemic around the world causing pneumonia and lower respiratory tract infections. Understanding the SARS-CoV-2 pathogenicity and mechanism of action, it is essential to depict the full repertoire of expressed viral proteins. The recent biological studies have highlighted the leader protein Nsp1 of SARS-CoV-2 importance in shutting down the host protein production. Besides it still enigmatic how Nsp1 regulate for translation. Here we report the novel structure of Nsp1 from SARS-CoV-2 in complex with SL1 region of 5′UTR of SARS-CoV-2 and its factual interaction is corroborated with enzyme kinetics and experimental binding affinity studies. The studies also address how the leader protein Nsp1 of SARS-CoV-2 recognises its self RNA towards the translational regulation by further recruitment of 40S ribosome. With the aid of molecular dynamics and simulations, we also modelled the real-time stability and functional dynamics of Nsp1/SL1 complex. The studies also report the potential inhibitors and its mode of action to block the viral protein/RNA complex formation. This built the fundamental in understanding the mechanism of first viral protein synthesised in the human cell to regulate the translation of self and host. Understanding the structure and mechanism of SARS-CoV-2 Nsp1& its interplay with the viral RNA and ribosome will open the arena of exploring the development of live attenuated vaccines and effective therapeutic targets for this disease.
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