Stratégies de formation de la structure coiffe chez les virus à ARN

Bouvet, Mickaël; Ferrón, François; Imbert, Isabelle; Gluais, Laure; Selisko, Barbara; Coutard, Bruno; Canard, Bruno; Decroly, Étienne

doi:10.1051/medsci/2012284021

Cited by 5 publications

(6 citation statements)

References 31 publications

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“…Nidoviruses have linear, single-stranded RNA genomes with positive polarity that contain a 5= cap structure and a 3= poly(A) tail (17). Several enzymes are involved in the formation of the 5= cap structure of viral RNA and host mRNA, including RNA triphosphatase, guanylyltransferase, N7-MTase, and 2=-O-MTase (1,2,4). In coronaviruses, the N7-and 2=-O-MTases have been studied in the most detail, and the two enzymes were found to play important roles in the modification of the viral cap structure (5,18,22), while the RNA helicase nsp13 of coronaviruses could function as an RNA triphosphatase (46).…”

Section: Discussionmentioning

confidence: 99%

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

“…A 5=-terminal cap structure, an N7-methylguanosine linked to the first templated nucleotide via a 5=-5= triphosphate bridge, is employed widely in viral and eukaryotic cellular mRNAs and plays a critical role in mRNA stability and translation (1)(2)(3). The basic cap-0 structure m7GpppN is formed by sequential reactions catalyzed by an RNA triphosphatase, a guanylyltransferase, and a guanine-N7-methyltransferase (N7-MTase) (1,2,4). In higher eukaryotes and most viruses, the cap-0 structure is further methylated at the ribose 2=-O position of the first nucleotide by ribose 2=-O-methyltransferase (2=-O-MTase) to form a cap-1 structure (m7GpppNm2) (4)(5)(6).…”

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

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Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Zeng

Wang

et al. 2016

J Virol

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The order Nidovirales currently comprises four virus families: Arteriviridae, Coronaviridae (divided into the subfamilies Coronavirinae and Torovirinae), Roniviridae, and the recently recognized Mesoniviridae. RNA cap formation and methylation have been best studied for coronaviruses, with emphasis on the identification and characterization of two virus-encoded methyltransferases (MTases) involved in RNA capping, a guanine-N7-MTase and a ribose-2=-O-MTase. Although bioinformatics analyses suggest that these MTases may also be encoded by other nidoviruses with large genomes, such as toroviruses and roniviruses, no experimental evidence has been reported thus far. In this study, we show that a ronivirus, gill-associated virus (GAV), encodes the 2=-O-MTase activity, although we could not detect 2=-O-MTase activity for the homologous protein of a torovirus, equine torovirus, which is more closely related to coronaviruses. Like the coronavirus 2=-O-MTase, the roniviral 2=-O-MTase harbors a catalytic K-D-K-E tetrad that is conserved among 2=-O-MTases and can target only the N7-methylated cap structure of adenylate-primed RNA substrates. However, in contrast with the coronavirus protein, roniviral 2=-O-MTase does not require a protein cofactor for stimulation of its activity and differs in its preference for several biochemical parameters, such as reaction temperature and pH. Furthermore, the ronivirus 2=-O-MTase can be targeted by MTase inhibitors. These results extend our current understanding of nidovirus RNA cap formation and methylation beyond the coronavirus family. IMPORTANCEMethylation of the 5=-cap structure of viral RNAs plays important roles in genome replication and evasion of innate recognition of viral RNAs by cellular sensors. It is known that coronavirus nsp14 acts as an N7-(guanine)-methyltransferase (MTase) and nsp16 as a 2=-O-MTase, which are involved in the modification of RNA cap structure. However, these enzymatic activities have not been shown for any other nidoviruses beyond coronaviruses in the order Nidovirales. In this study, we identified a 2=-Omethyltransferase encoded by ronivirus that shows common and unique features in comparison with that of coronaviruses. Ronivirus 2=-O-MTase does not need a protein cofactor for MTase activity, whereas coronavirus nsp16 needs the stimulating factor nsp10 for its full activity. The conserved K-D-K-E catalytic tetrad is identified in ronivirus 2=-O-MTase. These results extend our understanding of nidovirus RNA capping and methylation beyond coronaviruses and also strengthen the evolutionary and functional links between roniviruses and coronaviruses.

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Section: Discussionmentioning

confidence: 99%

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

See 1 more Smart Citation

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Zeng

Wang

et al. 2016

J Virol

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“…91 The C-terminal half of protein L is responsible for mRNA capping, and it contains an S-adenosyl-L-methioninedependent methyltransferase domain that likely works in this process. HHpred detects several structural templates (Fig.…”

Section: The Zinc-finger Domain Of Vp30mentioning

confidence: 99%

Predictive and comparative analysis of Ebolavirus proteins

2015

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Ebolavirus is the pathogen for Ebola Hemorrhagic Fever (EHF). This disease exhibits a high fatality rate and has recently reached a historically epidemic proportion in West Africa. Out of the 5 known Ebolavirus species, only Reston ebolavirus has lost human pathogenicity, while retaining the ability to cause EHF in long-tailed macaque. Significant efforts have been spent to determine the three-dimensional (3D) structures of Ebolavirus proteins, to study their interaction with host proteins, and to identify the functional motifs in these viral proteins. Here, in light of these experimental results, we apply computational analysis to predict the 3D structures and functional sites for Ebolavirus protein domains with unknown structure, including a zinc-finger domain of VP30, the RNA-dependent RNA polymerase catalytic domain and a methyltransferase domain of protein L. In addition, we compare sequences of proteins that interact with Ebolavirus proteins from RESTV-resistant primates with those from RESTV-susceptible monkeys. The host proteins that interact with GP and VP35 show an elevated level of sequence divergence between the RESTV-resistant and RESTV-susceptible species, suggesting that they may be responsible for host specificity. Meanwhile, we detect variable positions in protein sequences that are likely associated with the loss of human pathogenicity in RESTV, map them onto the 3D structures and compare their positions to known functional sites. VP35 and VP30 are significantly enriched in these potential pathogenicity determinants and the clustering of such positions on the surfaces of VP35 and GP suggests possible uncharacterized interaction sites with host proteins that contribute to the virulence of Ebolavirus.

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“…Most viral and eukaryotic cellular mRNA containing polyadenine region at 3′ terminal and a 5′terminal cap structure of N7-methyl-guanine moiety connected through 5′-5′ triphosphate bridge to the first transcribed nucleotide [ 6 , 7 ]. The 5′ terminal cap structure of mRNA plays a key role in protecting its degradation by 5′-exonuclease and efficient translation.…”

Section: Introductionmentioning

confidence: 99%

Computational guided drug repurposing for targeting 2′-O-ribose methyltransferase of SARS-CoV-2

et al. 2020

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Aims The recent outbreak of pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led the world towards a global health emergency. Currently, no proper medicine or effective treatment strategies are available; therefore, repurposing of FDA approved drugs may play an important role in overcoming the situation. Materials and methods The SARS-CoV-2 genome encodes for 2- O -methyltransferase (2′OMTase), which plays a key role in methylation of viral RNA for evading host immune system. In the present study, the protein sequence of 2′OMTase of SARS-CoV-2 was analyzed, and its structure was modeled by a comparative modeling approach and validated. The library of 3000 drugs was screened against the active site of 2′OMTase followed by re-docking analysis. The apo and ligand-bound 2′OMTase were further validated and analyzed by using molecular dynamics simulation. Key findings The modeled structure displayed the conserved characteristic fold of class I MTase family. The quality assessment analysis by SAVES server reveals that the modeled structure follows protein folding rules and of excellent quality. The docking analysis displayed that the active site of 2′OMTase accommodates an array of drugs, which includes alkaloids, antivirals, cardiac glycosides, anticancer, steroids, and other drugs. The redocking and MD simulation analysis of the best 5 FDA approved drugs reveals that these drugs form a stable conformation with the 2′OMTase. Significance The results suggested that these drugs may be used as potential inhibitors for 2′OMTase for combating the SARS-CoV-2 infection.

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Stratégies de formation de la structure coiffe chez les virus à ARN

Cited by 5 publications

References 31 publications

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Predictive and comparative analysis of Ebolavirus proteins

Computational guided drug repurposing for targeting 2′-O-ribose methyltransferase of SARS-CoV-2

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