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bioRxiv · 10.1101/2020.05.18.102467

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

Thoms, M.·Buschauer, R.·Ameismeier, M.·Koepke, L.·Denk, T.·Hirschenberger, M.·Kratzat, H.·Hayn, M.·Mackens-Kiani, T.·Cheng, J.·Stuerzel, C. M.·Froehlich, T.·Berninghausen, O.·Becker, T.·Kirchhoff, F.·Sparrer, K. M. J.·Beckmann, R.
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Abstract

SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association via an unknown mechanism. Here, we show that Nsp1 from SARS-CoV-2 binds to 40S and 80S ribosomes, resulting in shutdown of capped mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) of in vitro reconstituted Nsp1-40S and of native human Nsp1-ribosome complexes revealed that the Nsp1 C-terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks RIG-I-dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.

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Thoms, M., Buschauer, R., Ameismeier, M., Koepke, L., Denk, T., Hirschenberger, M., Kratzat, H., Hayn, M., Mackens-Kiani, T., Cheng, J., Stuerzel, C. M., Froehlich, T., Berninghausen, O., Becker, T., Kirchhoff, F., Sparrer, K. M. J., Beckmann, R.. 2020-05-18. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. https://doi.org/10.1101/2020.05.18.102467

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