Abstract

The  SARS-CoV-2 non-structural protein 1 (Nsp1), also referred to as the  host shutoff factor, suppresses host innate immune functions. By  combining cryo-electron microscopy  冷冻电子显微镜 and biochemistry, we show that  SARS-CoV-2 Nsp1 binds to the human 40S subunit in ribosomal complexes,  including the 43S pre-initiation complex and the non-translating 80S  ribosome. The protein inserts its C-terminal domain into the mRNA  channel, where it interferes with mRNA binding. We observe translation  inhibition in the presence of Nsp1 in an in vitro translation system and  in human cells. Based on the high-resolution structure of the 40S–Nsp1  complex, we identify residues of Nsp1 crucial for mediating translation  inhibition. We further show that the full-length 5′ untranslated region  of the genomic viral mRNA stimulates translation in vitro, suggesting  that SARS-CoV-2 combines global inhibition of translation by Nsp1 with  efficient translation of the viral mRNA to allow expression of viral  genes.