2015
DOI: 10.1073/pnas.1514978112
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Molecular basis for specific viral RNA recognition and 2′-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5)

Abstract: Dengue virus (DENV) causes several hundred million human infections and more than 20,000 deaths annually. Neither an efficacious vaccine conferring immunity against all four circulating serotypes nor specific drugs are currently available to treat this emerging global disease. Capping of the DENV RNA genome is an essential structural modification that protects the RNA from degradation by 5′ exoribonucleases, ensures efficient expression of viral proteins, and allows escape from the host innate immune response.… Show more

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Cited by 93 publications
(90 citation statements)
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“…The RNA polymerase structures from WNV (PDB #2HFZ)34, JEV (PDB #4K6M)35, DENV (PDB #5DTO)36 and HCV (PDB #4WTG)37 share 72, 70, 68, and 25% sequence identity, respectively, with the orthologous ZIKV enzyme. Despite its relatively low sequence identity to ZIKV, the HCV enzyme structure is complexed with sofosbuvir, and the amino acids residues that interact with the drug are highly conserved (approximately 80%) among the members of the Flaviviridae family37.…”
Section: Resultsmentioning
confidence: 99%
“…The RNA polymerase structures from WNV (PDB #2HFZ)34, JEV (PDB #4K6M)35, DENV (PDB #5DTO)36 and HCV (PDB #4WTG)37 share 72, 70, 68, and 25% sequence identity, respectively, with the orthologous ZIKV enzyme. Despite its relatively low sequence identity to ZIKV, the HCV enzyme structure is complexed with sofosbuvir, and the amino acids residues that interact with the drug are highly conserved (approximately 80%) among the members of the Flaviviridae family37.…”
Section: Resultsmentioning
confidence: 99%
“…The sulfate molecule bound via a cluster formed by arginines Arg43, Arg47, Arg63, and Arg90 (Fig. 2D) is closely located in between two phosphodiester groups of bound RNA in the structure described by Zhao et al (25) (namely P3 U and P4 U from chain B, with distances for S-P3 of 3 Å and for S-P4 of 4 Å). In this cluster formed by arginines Arg43, Arg47, Arg63, and Arg90, the main chain of ZIKV MTase (chain A) and DENV MTase (chain B [23]) structures overlap perfectly.…”
Section: Discussionmentioning
confidence: 77%
“…The homologous arginine residues were already reported to play a key role in the recruitment of RNA (25). Especially, residues corresponding to ZIKV MTase Arg63 and Arg90 (Arg57 and Arg84 in DENV, respectively) bind to the phosphate groups of the RNA during the 2=-O-methylation (25). The sulfate molecule bound via a cluster formed by arginines Arg43, Arg47, Arg63, and Arg90 (Fig.…”
Section: Discussionmentioning
confidence: 94%
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“…This is especially reflected in the low number of structures of proteins in complex with capped RNA (>1 nt) that have been determined to date. Currently, these structures include the human 2 ′ -O-ribose methyltransferase CMTr1 with a capped 4-mer that was produced by chemical coupling (Smietanski et al 2014), the 2 ′ -O-ribose methyltransferase of vaccinia virus with a capped 6-mer that was produced by in vitro transcription in the presence of a cap analog (Hodel et al 1998), the 2 ′ -O-ribose methyltransferase in the NS5 protein from dengue virus with an 8-mer cap-0 viral RNA that was produced using a cap analog (Zhao et al 2015), the dengue virus methyltransferase in complex with a 5 ′ -capped RNA 8-mer that was chemically synthesized (Yap et al 2010), and the innate immune receptor RIG-I that contains a chemically synthesized 24-nt-long capped hairpin RNA (Devarkar et al 2016). The high-resolution structural data available is thus confined to a small subset of the numerous enzymes and proteins that directly interact with the mRNA cap structure.…”
Section: Thementioning
confidence: 99%