Structural basis for translation inhibition by MERS-CoV Nsp1 reveals a conserved mechanism for betacoronaviruses
Swapnil C. Devarkar,
Michael Vetick,
Shravani Balaji,
Ivan B. Lomakin,
Luojia Yang,
Danni Jin,
Wendy V. Gilbert,
Sidi Chen,
Yong Xiong
Affiliations
Swapnil C. Devarkar
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Michael Vetick
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Shravani Balaji
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Ivan B. Lomakin
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
Luojia Yang
Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Danni Jin
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Wendy V. Gilbert
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Sidi Chen
Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Yong Xiong
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Corresponding author
Summary: All betacoronaviruses (β-CoVs) encode non-structural protein 1 (Nsp1), an essential pathogenicity factor that potently restricts host gene expression. Among the β-CoV family, MERS-CoV is the most distantly related member to SARS-CoV-2, and the mechanism for host translation inhibition by MERS-CoV Nsp1 remains controversial. Herein, we show that MERS-CoV Nsp1 directly interacts with the 40S ribosomal subunit. Using cryogenic electron microscopy (cryo-EM), we report a 2.6-Å structure of the MERS-CoV Nsp1 bound to the human 40S ribosomal subunit. The extensive interactions between C-terminal domain of MERS-CoV Nsp1 and the mRNA entry channel of the 40S ribosomal subunit are critical for its translation inhibition function. This mechanism of MERS-CoV Nsp1 is strikingly similar to SARS-CoV and SARS-CoV-2 Nsp1, despite modest sequence conservation. Our results reveal that the mechanism of host translation inhibition is conserved across β-CoVs and highlight a potential therapeutic target for the development of antivirals that broadly restrict β-CoVs.