ArticleProceedings of the National Academy of Sciences of the United States of America2021
Structure-function analysis of the nsp14 N7-guanine methyltransferase reveals an essential role in
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development-A Systematic Review.Viruses · 2022Pooled it
- Coronavirus NSP14 drives internal m7G modification to rewire host splicing and promote viral replication.Nucleic acids research · 2026Article
- Synergistic antiviral effects of structure-guided peptides and a mutagenic base analog on SARS-CoV-2 replication.Antimicrobial agents and chemotherapy · 2026Article
- Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase.RSC medicinal chemistry · 2026Article
- A structural roadmap for the formation of the coronavirus nsp3/nsp4 double membrane vesicle pore and its implications for polyprotein processing and replication/transcription.Journal of virology · 2025Article
- SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation.Nature communications · 2025Article
- Design and Synthesis of Pyrazoline Inhibitors of SARS-CoV‑2 NSP14.ACS medicinal chemistry letters · 2025Article
- Discovery of Novel Isofunctional SARS-CoV‑2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening.ACS medicinal chemistry letters · 2025Article
- Article
- Au(I)-based compounds inhibit nsp14/nsp10 and nsp13 (helicase) to exert anti-SARS-CoV-2 properties.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2025Article
- Unveiling the structural and functional implications of uncharacterized NSPs and variations in the molecular toolkit across arteriviruses.NAR genomics and bioinformatics · 2025Article
- Article
- Perspective for Drug Discovery Targeting SARS Coronavirus Methyltransferases: Function, Structure and Inhibition.Journal of medicinal chemistry · 2024Review
- A universal fluorescence polarization high throughput screening assay to target the SAM-binding sites of SARS-CoV-2 and other viral methyltransferases.Emerging microbes & infections · 2023Article
- MAb Targeting a Link Between ExoN and MTase of TGEV NSP14.Monoclonal antibodies in immunodiagnosis and immunotherapy · 2023Article
- Article
- Structures of SARS-CoV-2 N7-methyltransferase with DOT1L and PRMT7 inhibitors provide a platform for new antivirals.PLoS pathogens · 2023Article
- Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication.Microbiology and molecular biology reviews : MMBR · 2022Review
- A Temperature-Sensitive Recombinant of Avian Coronavirus Infectious Bronchitis Virus Provides Complete Protection against Homologous Challenge.Journal of virology · 2022Article
- Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase.ACS medicinal chemistry letters · 2022Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their messenger RNAs (mRNAs), protect them from degradation by cellular 5' exoribonucleases (ExoNs), and escape innate immune sensing. The CoV nonstructural protein 14 (nsp14) is a bifunctional replicase subunit harboring an N-terminal 3'-to-5' ExoN domain and a C-terminal (N7-guanine)-methyltransferase (N7-MTase) domain that is presumably involved in viral mRNA capping. Here, we aimed to integrate structural, biochemical, and virological data to assess the importance of conserved N7-MTase residues for nsp14's enzymatic activities and virus viability. We revisited the crystal structure of severe acute respiratory syndrome (SARS)-CoV nsp14 to perform an in silico comparative analysis between betacoronaviruses. We identified several residues likely involved in the formation of the N7-MTase catalytic pocket, which presents a fold distinct from the Rossmann fold observed in most known MTases. Next, for SARS-CoV and Middle East respiratory syndrome CoV, site-directed mutagenesis of selected residues was used to assess their importance for in vitro enzymatic activity. Most of the engineered mutations abolished N7-MTase activity, while not affecting nsp14-ExoN activity. Upon reverse engineering of these mutations into different betacoronavirus genomes, we identified two substitutions (R310A and F426A in SARS-CoV nsp14) abrogating virus viability and one mutation (H424A) yielding a crippled phenotype across all viruses tested. Our results identify the N7-MTase as a critical enzyme for betacoronavirus replication and define key residues of its catalytic pocket that can be targeted to design inhibitors with a potential pan-coronaviral activity spectrum.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.