Structural and Functional Basis of the Fidelity of Nucleotide Selection by Flavivirus RNA-Dependent RNA Polymerases

Viral RNA-dependent RNA polymerases (RdRps) play a central role not only in viral replication, but also in the genetic evolution of viral RNAs. After binding to an RNA template and selecting 5′-triphosphate ribonucleosides, viral RdRps synthesize an RNA copy according to Watson-Crick base-pairing rules. The copy process sometimes deviates from both the base-pairing rules specified by the template and the natural ribose selectivity and, thus, the process is error-prone due to the intrinsic (in)fidelity of viral RdRps. These enzymes share a number of conserved amino-acid sequence strings, called motifs A–G, which can be defined from a structural and functional point-of-view. A co-relation is gradually emerging between mutations in these motifs and viral genome evolution or observed mutation rates. Here, we review our current knowledge on these motifs and their role on the structural and mechanistic basis of the fidelity of nucleotide selection and RNA synthesis by Flavivirus RdRps.

• Publication year

  2018

• Venue

  Viruses

• Publication date

  2018-01-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3390/v10020059PMID 29385764PMCID 5850366
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Structure of large fragment of Escherichia coli DNA polymerase I complexed with dTMP

  2020cited by this paper
• Crystal

  2019cited by this paper
• Transcription fidelity and its roles in the cell

  2018cited by this paper
• Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase

  2017cited by this paper
• Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5

  2017cited by this paper
• In vitro Selection of Resistance to Sofosbuvir in HCV Replicons of Genotype-1 to -6

  2017cited by this paper
• Picornaviral polymerase structure, function, and fidelity modulation.

  2017cited by this paper
• A structural view of the RNA-dependent RNA polymerases from the Flavivirus genus.

  2017cited by this paper
• Triphosphate Reorientation of the Incoming Nucleotide as a Fidelity Checkpoint in Viral RNA-dependent RNA Polymerases*

  2017cited by this paper
• Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors

  2017influential reference
• Attenuation of Foot-and-Mouth Disease Virus by Engineered Viral Polymerase Fidelity

  2017cited by this paper
• Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase

  2017cited by this paper
• The crystal structure of Zika virus NS5 reveals conserved drug targets

  2017cited by this paper
• Signatures of Nucleotide Analog Incorporation by an RNA-Dependent RNA Polymerase Revealed Using High-Throughput Magnetic Tweezers

  2017cited by this paper
• Structure and function of the Zika virus full-length NS5 protein

  2017cited by this paper
• Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus

  2017cited by this paper
• Mutagen resistance and mutation restriction of St. Louis encephalitis virus.

  2017cited by this paper
• Substrate selectivity of Dengue and Zika virus NS5 polymerase towards 2′‐modified nucleotide analogues

  2017cited by this paper
• Design of a Genetically Stable High Fidelity Coxsackievirus B3 Polymerase That Attenuates Virus Growth in Vivo*

  2016cited by this paper
• Mechanisms of viral mutation

  2016influential reference
• Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor.

  2016cited by this paper
• Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling

  2016influential reference
• Approved Antiviral Drugs over the Past 50 Years

  2016cited by this paper
• Homology-Based Identification of a Mutation in the Coronavirus RNA-Dependent RNA Polymerase That Confers Resistance to Multiple Mutagens

  2016cited by this paper
• Dengue Virus Nonstructural Protein 5 (NS5) Assembles into a Dimer with a Unique Methyltransferase and Polymerase Interface

  2016cited by this paper
• Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation

  2016influential reference
• DNA Replication-A Matter of Fidelity.

  2016cited by this paper
• A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication

  2015influential reference
• Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

  2015cited by this paper
• Structural basis for RNA replication by the hepatitis C virus polymerase

  2015cited by this paper
• Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes

  2015influential reference
• RNA Virus Population Diversity, an Optimum for Maximal Fitness and Virulence*

  2014cited by this paper
• Inhibition of viral RNA polymerases by nucleoside and nucleotide analogs: therapeutic applications against positive-strand RNA viruses beyond hepatitis C virus

  2014cited by this paper
• Structure-Function Relationships Underlying the Replication Fidelity of Viral RNA-Dependent RNA Polymerases

  2014influential reference
• Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

  2014cited by this paper
• Resistance to nucleotide analogue inhibitors of hepatitis C virus NS5B: mechanisms and clinical relevance.

  2014cited by this paper
• The Interface between Methyltransferase and Polymerase of NS5 Is Essential for Flavivirus Replication

  2014cited by this paper
• Correlation Between Mutation Rate and Genome Size in Riboviruses: Mutation Rate of Bacteriophage Qβ

  2013cited by this paper
• A Crystal Structure of the Dengue Virus Non-structural Protein 5 (NS5) Polymerase Delineates Interdomain Amino Acid Residues That Enhance Its Thermostability and de Novo Initiation Activities*

  2013cited by this paper
• Mechanism of the nucleotidyl-transfer reaction in DNA polymerase revealed by time-resolved protein crystallography

  2013cited by this paper
• Crystal Structure of the Full-Length Japanese Encephalitis Virus NS5 Reveals a Conserved Methyltransferase-Polymerase Interface

  2013cited by this paper
• Conformational Flexibility of the Dengue Virus RNA-Dependent RNA Polymerase Revealed by a Complex with an Inhibitor

  2013cited by this paper
• NTP-mediated nucleotide excision activity of hepatitis C virus RNA-dependent RNA polymerase

  2013influential reference
• RNA-dependent RNA polymerase of Japanese encephalitis virus binds the initiator nucleotide GTP to form a mechanistically important pre-initiation state

  2013cited by this paper
• Vaccine-derived Mutation in Motif D of Poliovirus RNA-dependent RNA Polymerase Lowers Nucleotide Incorporation Fidelity*

  2013cited by this paper
• Role of motif B loop in allosteric regulation of RNA-dependent RNA polymerization activity.

  2013cited by this paper
• Residues Arg283, Arg285, and Ile287 in the Nucleotide Binding Pocket of Bovine Viral Diarrhea Virus NS5B RNA Polymerase Affect Catalysis and Fidelity

  2012cited by this paper
• Molecular Basis for Nucleotide Conservation at the Ends of the Dengue Virus Genome

  2012cited by this paper
• Coxsackievirus B3 mutator strains are attenuated in vivo

  2012cited by this paper
• Antimicrobial Strategies

  2012cited by this paper
• Motif D of viral RNA-dependent RNA polymerases determines efficiency and fidelity of nucleotide addition.

  2012cited by this paper
• Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance

  2011cited by this paper
• The F1 Motif of Dengue Virus Polymerase NS5 Is Involved in Promoter-Dependent RNA Synthesis

  2011cited by this paper
• Viral mutation and substitution: units and levels.

  2011cited by this paper
• Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase

  2010influential reference
• Characterization of the Elongation Complex of Dengue Virus RNA Polymerase

  2010cited by this paper
• Fidelity Variants of RNA Dependent RNA Polymerases Uncover an Indirect, Mutagenic Activity of Amiloride Compounds

  2010cited by this paper
• Structure of Foot-and-Mouth Disease Virus Mutant Polymerases with Reduced Sensitivity to Ribavirin

  2010cited by this paper
• Viral Mutation Rates

  2010cited by this paper
• Long-range interaction networks in the function and fidelity of poliovirus RNA-dependent RNA polymerase studied by nuclear magnetic resonance.

  2010cited by this paper
• Further Insights into the Roles of GTP and the C Terminus of the Hepatitis C Virus Polymerase in the Initiation of RNA Synthesis*

  2010influential reference
• RNA Sequences and Structures Required for the Recruitment and Activity of the Dengue Virus Polymerase*

  2010cited by this paper
• Characterization of Dengue Virus Resistance to Brequinar in Cell Culture

  2010influential reference
• Jalview Version 2—a multiple sequence alignment editor and analysis workbench

  2009cited by this paper
• rtracklayer: an R package for interfacing with genome browsers

  2009cited by this paper
• RNA polymerase fidelity and transcriptional proofreading.

  2009cited by this paper
• Nucleic acid polymerases employ a general acid for nucleotidyl transfer

  2008cited by this paper
• Structural and Functional Studies of the Promoter Element for Dengue Virus RNA Replication

  2008cited by this paper
• Crystal Structure of the RNA Polymerase Domain of the West Nile Virus Non-structural Protein 5*

  2007cited by this paper
• Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution

  2007cited by this paper
• Sequential structures provide insights into the fidelity of RNA replication

  2007cited by this paper
• Two proton transfers in the transition state for nucleotidyl transfer catalyzed by RNA- and DNA-dependent RNA and DNA polymerases

  2007cited by this paper
• Comparative mechanistic studies of de novo RNA synthesis by flavivirus RNA-dependent RNA polymerases.

  2006cited by this paper
• Regulation of DNA repair fidelity by molecular checkpoints: "gates" in DNA polymerase beta's substrate selection.

  2006cited by this paper
• General Catalytic Deficiency of Hepatitis C Virus RNA Polymerase with an S282T Mutation and Mutually Exclusive Resistance towards 2′-Modified Nucleotide Analogues

  2006cited by this paper
• Intracellular Substrates for the Primer-Unblocking Reaction by Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Detection and Quantitation in Extracts from Quiescent- and Activated-Lymphocyte Subpopulations

  2005cited by this paper
• Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective☆

  2004cited by this paper
• Structural basis for substrate selection by t7 RNA polymerase.

  2004cited by this paper
• WebLogo: a sequence logo generator.

  2004influential reference
• A structural and primary sequence comparison of the viral RNA-dependent RNA polymerases.

  2003cited by this paper
• Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro*

  2003cited by this paper
• The Palm Subdomain-based Active Site is Internally Permuted in Viral RNA-dependent RNA Polymerases of an Ancient Lineage

  2002cited by this paper
• Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases.

  2002cited by this paper
• Implications of high RNA virus mutation rates: lethal mutagenesis and the antiviral drug ribavirin.

  2002cited by this paper
• The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen

  2000cited by this paper
• Mutational Analysis of Bovine Viral Diarrhea Virus RNA-Dependent RNA Polymerase

  1999cited by this paper
• Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site

  1999cited by this paper
• Mutation rates among RNA viruses.

  1999cited by this paper
• Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.

  1999cited by this paper
• Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.

  1999cited by this paper
• A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase.

  1999cited by this paper
• RNA-dependent RNA polymerase of hepatitis C virus.

  1996cited by this paper
• A single residue in DNA polymerases of the Escherichia coli DNA polymerase I family is critical for distinguishing between deoxy- and dideoxyribonucleotides.

  1995cited by this paper
• Physiological concentrations of purines and pyrimidines

  1994cited by this paper
• Rates of spontaneous mutation among RNA viruses.

  1993cited by this paper
• A constant rate of spontaneous mutation in DNA-based microbes.

  1991cited by this paper
• Identification of four conserved motifs among the RNA‐dependent polymerase encoding elements.

  1989cited by this paper

• Substitutions M478K and A482G in the polymerase of yellow fever virus confer resistance to sofosbuvir and uprifosbuvir in vitro.

  2026cites this paper
• Mechanism of Inhibition of the Active Triphosphate Form of 2′-α-Fluoro,2′-β-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase

  2025cites this paper
• Crystallographic fragment screening of the dengue virus polymerase reveals multiple binding sites for the development of non-nucleoside antiflavivirals

  2025cites this paper
• Exploration of effective pharmacological inhibitors for NS5 protein through computational approach: A strategy to combat the neglected Kyasanur forest disease virus

  2025cites this paper
• Mapping the impact of 1'-, 2'- and 4'-nucleotide modifications on the Respiratory Syncytial Virus RNA-dependent RNA polymerase.

  2025cites this paper
• Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals

  2025cites this paper
• Structure of the RNA-dependent RNA polymerase P2 from the cystovirus φ8

  2024cites this paper
• Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis

  2024cites this paper
• Improvement in the potency of a N1-methylpseudouridine-modified self-amplifying RNA through mutations in the RNA-dependent RNA polymerase

  2024cites this paper
• Tertiary Structures of Haseki Tick Virus Nonstructural Proteins Are Similar to Those of Orthoflaviviruses

  2024cites this paper
• The effects of Remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase.

  2024cites this paper
• Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase

  2023cites this paper
• Presence, Location and Conservation of Putative G-Quadruplex Forming Sequences in Arboviruses Infecting Humans

  2023cites this paper
• Unravelling the epidemiological diversity of Zika virus by analyzing key protein variations

  2023cites this paper
• Intrinsic factors driving mosquito vector competence and viral evolution: a review

  2023cites this paper
• RNA-Dependent RNA Polymerase of the Second Human Pegivirus Exhibits a High-Fidelity Feature

  2022cites this paper
• Silent codon positions in the A-rich HIV RNA genome that do not easily become A: Restrictions imposed by the RNA sequence and structure

  2022cites this paper
• Biological Characterization of Yellow Fever Viruses Isolated From Non-human Primates in Brazil With Distinct Genomic Landscapes

  2022cites this paper
• A Review on the New Indication of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in the Treatment of Coronavirus Disease 2019.

  2022cites this paper
• Rifapentine is an entry and replication inhibitor against yellow fever virus both in vitro and in vivo

  2022cites this paper
• 2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

  2022cites this paper
• The Role of the Flavivirus Replicase in Viral Diversity and Adaptation

  2022cites this paper
• Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2

  2022cites this paper
• Inhibition of Viral RNA-Dependent RNA Polymerases by Nucleoside Inhibitors: An Illustration of the Unity and Diversity of Mechanisms

  2022cites this paper
• COVID-19 infection with keratitis as the first clinical manifestation.

  2022cites this paper
• A novel mechanism of enhanced transcription activity and fidelity for influenza A viral RNA-dependent RNA polymerase

  2021cites this paper
• Global surveillance of potential antiviral drug resistance in SARS-CoV-2: proof of concept focussing on the RNA-dependent RNA polymerase

  2021cites this paper
• Potential COVID‐19 Therapeutic Agents and Vaccines: An Evidence‐Based Review

  2021cites this paper
• Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance

  2021cites this paper
• Dissecting nucleotide selectivity in viral RNA polymerases

  2021influential citation
• The enzymes for genome size increase and maintenance of large (+)RNA viruses.

  2021cites this paper
• Snapshots of a Non-Canonical RdRP in Action

  2021cites this paper
• Allosteric and dynamic control of RNA-dependent RNA polymerase function and fidelity.

  2021cites this paper
• Suramin, penciclovir, and anidulafungin exhibit potential in the treatment of COVID-19 via binding to nsp12 of SARS-CoV-2

  2021cites this paper
• Plant-Derived Natural Non-Nucleoside Analog Inhibitors (NNAIs) against RNA-Dependent RNA Polymerase Complex (nsp7/nsp8/nsp12) of SARS-CoV-2

  2021cites this paper
• West Nile Virus fidelity modulates the capacity for host cycling and adaptation.

  2020cites this paper
• An African tick flavivirus forming an independent clade exhibits unique exoribonuclease-resistant RNA structures in the genomic 3′-untranslated region

  2020cites this paper
• Rate-limiting pyrophosphate release by hepatitis C virus polymerase NS5B improves fidelity

  2020influential citation
• An interferon lambda 4-associated variant in the hepatitis C virus RNA polymerase affects viral replication in infected cells

  2020cites this paper
• Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir

  2020cites this paper
• Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery

  2020cites this paper
• Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

  2020cites this paper
• A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19

  2020cites this paper
• A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

  2020cites this paper
• Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

  2020cites this paper
• Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

  2020cites this paper
• Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

  2020cites this paper
• Energy Transfer as A Driving Force in Nucleic Acid–Protein Interactions

  2019cites this paper
• Motif V regulates energy transduction between the flavivirus NS3 ATPase and RNA-binding cleft

  2019cites this paper
• Motif V acts as a Regulator of Energy Transduction Between the Flavivirus NS3 ATPase and RNA Binding Cleft

  2019cites this paper
• Phylogenetic surveillance of travel-related Zika virus infections through whole-genome sequencing methods

  2019cites this paper
• Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters

  2019cites this paper
• Applications of sequencing technologies in monitoring the evolution and transmission of viral pathogens

  2019cites this paper
• A Comprehensive Superposition of Viral Polymerase Structures

  2019cites this paper
• Structure of the yellow fever NS5 protein reveals conserved drug targets shared among flaviviruses.

  2019cites this paper
• Calicivirus RNA-Dependent RNA Polymerases: Evolution, Structure, Protein Dynamics, and Function

  2019cites this paper
• The hepatitis C virus RNA-dependent RNA polymerase directs incoming nucleotides to its active site through magnesium-dependent dynamics within its F motif

  2019cites this paper