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TitleStructural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2.
Journal, issue, pagesScience, Vol. 369, Issue 6508, Page 1249-1255, Year 2020
Publish dateSep 4, 2020
AuthorsMatthias Thoms / Robert Buschauer / Michael Ameismeier / Lennart Koepke / Timo Denk / Maximilian Hirschenberger / Hanna Kratzat / Manuel Hayn / Timur Mackens-Kiani / Jingdong Cheng / Jan H Straub / Christina M Stürzel / Thomas Fröhlich / Otto Berninghausen / Thomas Becker / Frank Kirchhoff / Konstantin M J Sparrer / Roland Beckmann /
PubMed AbstractSevere 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 ...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 40 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 Nsp1-40 and various native Nsp1-40 and -80 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.
External linksPubMed:32680882 / Publisher's page
KeywordsBetacoronavirus / Binding Sites / Coronavirus Infections / Cryoelectron Microscopy / DDX58 protein, human / DEAD Box Protein 58 / Humans / Immune Evasion / Immunity, Innate / Interferon-beta / Models, Molecular / NSP1 protein, SARS-CoV-2 / Pandemics / Pneumonia, Viral / Protein Binding / Protein Biosynthesis / Protein Domains / Protein Interaction Domains and Motifs / Protein Structure, Secondary / RNA, Messenger / Ribosome Subunits, Small, Eukaryotic / Viral Nonstructural Proteins / VIRAL PROTEIN / Translational Inhibition / SARS-CoV-2 / Human Ribosome
MethodsEM (single particle)
Resolution2.6 - 3.2 A
Structure data

EMDB-11276:
SARS-CoV-2 Nsp1 bound to the human 40S ribosomal subunit

EMDB-11288:
SARS-CoV-2 Nsp1 bound to the human CCDC124-80S-EBP1 ribosome complex

EMDB-11289:
SARS-CoV-2 Nsp1 bound to the human CCDC124-80S-eERF1 ribosome complex

EMDB-11292:
SARS-CoV-2 Nsp1 bound to the human LYAR-80S ribosome complex

EMDB-11299:
SARS-CoV-2 Nsp1 bound to the human LYAR-80S-eEF1a ribosome complex

EMDB-11301:
SARS-CoV-2 Nsp1 bound to a pre-40S-like ribosome complex

EMDB-11310:
SARS-CoV-2 Nsp1 bound to a pre-40S-like ribosome complex - state 2

EMDB-11325:
SARS-CoV-2 Nsp1 bound to a human 43S preinitiation ribosome complex - state 1

EMDB-11335:
SARS-CoV-2 Nsp1 bound to a human 43S preinitiation ribosome complex - state 2

PDB-6zlw:
SARS-CoV-2 Nsp1 bound to the human 40S ribosomal subunit

PDB-6zm7:
SARS-CoV-2 Nsp1 bound to the human CCDC124-80S-EBP1 ribosome complex

PDB-6zme:
SARS-CoV-2 Nsp1 bound to the human CCDC124-80S-eERF1 ribosome complex

PDB-6zmi:
SARS-CoV-2 Nsp1 bound to the human LYAR-80S ribosome complex

PDB-6zmo:
SARS-CoV-2 Nsp1 bound to the human LYAR-80S-eEF1a ribosome complex

PDB-6zmt:
SARS-CoV-2 Nsp1 bound to a pre-40S-like ribosome complex

PDB-6zn5:
SARS-CoV-2 Nsp1 bound to a pre-40S-like ribosome complex - state 2

PDB-6zon:
SARS-CoV-2 Nsp1 bound to a human 43S preinitiation ribosome complex - state 1

PDB-6zp4:
SARS-CoV-2 Nsp1 bound to a human 43S preinitiation ribosome complex - state 2

Chemicals

ChemComp-ZN:
ZINC ION / Zinc

ChemComp-MG:
MAGNESIUM ION / Magnesium

ChemComp-SF4:
IRON/SULFUR CLUSTER / Iron–sulfur cluster

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
  • Human (human)
  • 2019-nCoV (virus)

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