ArticleJournal of virology2022
The SARS-CoV nsp12 Polymerase Active Site Is Tuned for Large-Genome Replication.
Article in Journal of virology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Copy-back RNA synthesis by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.Science advances · 2026Article
- Preferential remdesivir triphosphate incorporation by SARS-CoV-2 polymerase is altered to ATP by the S759A mutation.Communications biology · 2026Article
- Structural basis for selective remdesivir incorporation by SARS-CoV-2 polymerase, and S759A resistance.Research square · 2025Article
- Template switching by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.bioRxiv : the preprint server for biology · 2025Article
- Therapeutic applications of interface-mimicking peptides for targeting the SARS-CoV-2 NSP12-NSP8 RdRp complex.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Single-step discovery of high-affinity RNA ligands by UltraSelex.Nature chemical biology · 2025Article
- Genome-Wide Interrogation of SARS-CoV-2 RNA-Protein Interactions Uncovers Hidden Regulatory Sites.bioRxiv : the preprint server for biology · 2025Article
- A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent.Nucleic acids research · 2025Article
- Article
- Review
- An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode.Nature communications · 2024Article
- Quasispecies theory and emerging viruses: challenges and applications.Npj viruses · 2024Review
- Adenosine modifications impede SARS-CoV-2 RNA-dependent RNA transcription.RNA (New York, N.Y.) · 2024Article
- A genus-specific nsp12 region impacts polymerase assembly in Alpha- and Gammacoronaviruses.bioRxiv : the preprint server for biology · 2024Article
- An alphacoronavirus polymerase structure reveals conserved replication factor functions.Nucleic acids research · 2024Article
- An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex.Nucleic acids research · 2024Article
- Comparing the molecular evolution and recombination patterns of predominant PRRSV-2 lineages co-circulating in China.Frontiers in microbiology · 2024Article
- Studying the intersection of nucleoside modifications and SARS-CoV-2 RNA-dependent RNA transcription using an in vitro reconstituted system.Methods in enzymology · 2024Article
- Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2.Antiviral research · 2023Review
- Progress on COVID-19 Chemotherapeutics Discovery and Novel Technology.Molecules (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Positive-strand RNA viruses replicate their genomes using virally encoded RNA-dependent RNA polymerases (RdRP) with a common active-site structure and closure mechanism upon which replication speed and fidelity can evolve to optimize virus fitness. Coronaviruses (CoV) form large multicomponent RNA replication-transcription complexes containing a core RNA synthesis machine made of the nsp12 RdRP protein with one nsp7 and two nsp8 proteins as essential subunits required for activity. We show that assembly of this complex can be accelerated 5-fold by preincubation of nsp12 with nsp8 and further optimized with the use of a novel nsp8L7 heterodimer fusion protein construct. Using rapid kinetics methods, we measure elongation rates of up to 260 nucleotides (nt)/s for the core replicase, a rate that is unusually fast for a viral polymerase. To address the origin of this fast rate, we examined the roles of two CoV-specific residues in the RdRP active site: Ala547, which replaces a conserved glutamate above the bound NTP, and Ser759, which mutates the palm domain GDD sequence to SDD. Our data show that Ala547 allows for a doubling of replication rate, but this comes at a fidelity cost that is mitigated by using a SDD sequence in the palm domain. Our biochemical data suggest that fixation of mutations in polymerase motifs F and C played a key role in nidovirus evolution by tuning replication rate and fidelity to accommodate their large genomes.
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Registered trials
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 OpenQuestion graph.