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

Thoms, Matthias; Buschauer, Robert; Ameismeier, Michael; Koepke, Lennart; Denk, Timo; Hirschenberger, Maximilian; Kratzat, Hanna; Hayn, Manuel; Mackens-Kiani, Timur; Cheng, Jingdong; Straub, Jan H.; Stürzel, Christina M.; Fröhlich, Thomas; Berninghausen, Otto; Becker, Thomas; Kirchhoff, Frank; Sparrer, Konstantin M. J. und Beckmann, Roland (2020): Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. In: Science, Vol. 369, No. 6508: pp. 1249-1255

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1), which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of messenger RNA (mRNA) translation both in vitro and in cells. Structural analysis by cryo-electron microscopy of in vitro-reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks retinoic acid-inducible gene 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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0036-8075
• Language: English