ArticleThe Journal of biological chemistry2016
Design of a Genetically Stable High Fidelity Coxsackievirus B3 Polymerase That Attenuates Virus Growth in Vivo.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 41 citations in OpenAlex.
- The SARS-CoV nsp12 Polymerase Active Site Is Tuned for Large-Genome Replication.Journal of virology · 2022Article
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- A novel mechanism of enhanced transcription activity and fidelity for influenza A viral RNA-dependent RNA polymerase.Nucleic acids research · 2021Article
- Tradeoffs for a viral mutant with enhanced replication speed.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Polymerase Fidelity Contributes to Foot-and-Mouth Disease Virus Pathogenicity and TransmissibilityJournal of virology · 2020Article
- Picornaviral polymerase domain exchanges reveal a modular basis for distinct biochemical activities of viral RNA-dependent RNA polymerases.The Journal of biological chemistry · 2020Article
- An Extended Primer Grip of Picornavirus Polymerase Facilitates Sexual RNA Replication Mechanisms.Journal of virology · 2020Article
- A Low Fidelity Virus Shows Increased Recombination during the Removal of an Alphavirus Reporter Gene.Viruses · 2020Article
- Article
- A nucleobase-binding pocket in a viral RNA-dependent RNA polymerase contributes to elongation complex stability.Nucleic acids research · 2020Article
- Tyr82 Amino Acid Mutation in PB1 Polymerase Induces an Influenza Virus Mutator Phenotype.Journal of virology · 2019Article
- Rational Control of Poliovirus RNA-Dependent RNA Polymerase Fidelity by Modulating Motif-D Loop Conformational Dynamics.Biochemistry · 2019Article
- Picornavirus RNA Recombination Counteracts Error Catastrophe.Journal of virology · 2019Article
- Enterovirus A71 Containing Codon-Deoptimized VP1 and High-Fidelity Polymerase as Next-Generation Vaccine Candidate.Journal of virology · 2019Article
- Article
- Chikungunya Virus Fidelity Variants Exhibit Differential Attenuation and Population Diversity in Cell Culture and Adult Mice.Journal of virology · 2019Article
- Evolutionary and Structural Overview of Human Picornavirus Capsid Antibody Evasion.Frontiers in cellular and infection microbiology · 2019Review
- A unique intra-molecular fidelity-modulating mechanism identified in a viral RNA-dependent RNA polymerase.Nucleic acids research · 2018Article
- RNA Virus Fidelity Mutants: A Useful Tool for Evolutionary Biology or a Complex Challenge?Viruses · 2018Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Positive strand RNA viruses replicate via a virally encoded RNA-dependent RNA polymerase (RdRP) that uses a unique palm domain active site closure mechanism to establish the canonical two-metal geometry needed for catalysis. This mechanism allows these viruses to evolutionarily fine-tune their replication fidelity to create an appropriate distribution of genetic variants known as a quasispecies. Prior work has shown that mutations in conserved motif A drastically alter RdRP fidelity, which can be either increased or decreased depending on the viral polymerase background. In the work presented here, we extend these studies to motif D, a region that forms the outer edge of the NTP entry channel where it may act as a nucleotide sensor to trigger active site closure. Crystallography, stopped-flow kinetics, quench-flow reactions, and infectious virus studies were used to characterize 15 engineered mutations in coxsackievirus B3 polymerase. Mutations that interfere with the transport of the metal A Mg(2+) ion into the active site had only minor effects on RdRP function, but the stacking interaction between Phe(364) and Pro(357), which is absolutely conserved in enteroviral polymerases, was found to be critical for processive elongation and virus growth. Mutating Phe(364) to tryptophan resulted in a genetically stable high fidelity virus variant with significantly reduced pathogenesis in mice. The data further illustrate the importance of the palm domain movement for RdRP active site closure and demonstrate that protein engineering can be used to alter viral polymerase function and attenuate virus growth and pathogenesis.
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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.