ScienceMolecular BiologyPeer-reviewed journal article
Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2
Matthias ThomsiD, Robert BuschaueriD, Michael AmeismeieriD, Lennart KoepkeiD, Timo DenkiD, Maximilian HirschenbergeriD, Hanna KratzatiD, Manuel HayniD, Timur Mackens‐KianiiD, Jingdong ChengiD, Jan Hendrik Straub, Christina Martina Stürzel, Thomas FröhlichiD, Otto BerninghauseniD, Thomas A. BeckeriD, Frank KirchhoffiD, Konstantin M. J. SparreriD, Roland BeckmanniD
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.
- organism: human
- assay: protein structure
- research focus: protein structure prediction
- approach: experimental assay
- Citations
- 885
- FWCI
- 53.56
- Field percentile
- top 1%
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