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Conserved motifs in the flavivirus NS3 RNA helicase enzyme

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Abstract Flaviviruses are a major health concern because over half of the world population is at risk of infection and there are very few antiviral therapeutics to treat diseases resulting from infection. Replication is an essential part of the flavivirus survival. One of the viral proteins, NS3 helicase, is critical for unwinding the double stranded RNA intermediate during flaviviral replication. The helicase performs the unwinding of the viral RNA intermediate structure in an ATP‐dependent manner. NS3 helicase is a member of the Viral/DEAH‐like subfamily of the superfamily 2 helicase containing eight highly conserved structural motifs (I, Ia, II, III, IV, IVa, V, and VI) localized between the ATP‐binding and RNA‐binding pockets. Of these structural motifs only three are well characterized for function in flaviviruses (I, II, and VI). The roles of the other structural motifs are not well understood for NS3 helicase function, but comparison of NS3 with other superfamily 2 helicases within the viral/DEAH‐like, DEAH/RHA, and DEAD‐box subfamilies can be used to elucidate the roles of these structural motifs in the flavivirus NS3 helicase. This review aims to summarize the role of each conserved structural motif within flavivirus NS3 in RNA helicase function. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease
Flavivirus NS3 helicase interactions with ATP within the ATP binding pocket. Motif I (orange), Motif II (magenta), and Motif VI (royal blue) form the ATP binding pocket within the NS3 helicase. Residue K199 from Motif I interacts with the ATP β‐phosphate, while T200 from Motif I and D284 from Motif II coordinates with the Mg2+ ion. E285 from Motif II stabilizes interactions with the lytic water. R460 from Motif VI interacts with the lytic water
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Flavivirus NS3 helicase structure (DENV4 NS3 helicase; PDB code 2JLV). NS3 helicase consists of three subdomains (labeled as 1, 2, and 3). Within subdomains 1 and 2, there are eight highly conserved SF2 helicase structural motifs. These motifs are highlighted as follows: Motif I in orange; Motif Ia in dark green; Motif II in magenta; Motif III in lime green; Motif IV in blue; Motif IVa in red; Motif V in purple; and Motif VI in royal blue. Additionally, NS3 helicase substrates, ATP and ssRNA, are bound in their respective binding pockets. The ATP binding pocket is located between subdomains 1 and 2; the RNA binding cleft is located between subdomain 3 and subdomains 1 and 2; and the helical gate and β‐wedge are located between subdomain 2 and 3
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Flavivirus life cycle. The cycle begins with viral attachment and entry via clathrin‐mediated endocytosis. Following entry, flaviviruses undergo endosomal fusion and genomic release into the cytoplasm. The viral RNA is trafficked to the endoplasmic reticulum for translation, replication, and assembly. Viral maturation occurs as the virion travels through the Golgi leading to secretion of the mature virion from the cell via exocytosis. The inset focuses on the viral processes that occur at the endoplasmic reticulum membrane. This figure was created with BioRender.com
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Flavivirus NS3 helicase interactions with ssRNA within the RNA binding cleft. Subdomain 3 forms the RNA binding cleft with subdomains 1 and 2. Residues within Motif Ia (dark green), Motif IV (blue), Motif IVa (red), and Motif V (purple) interact with ssRNA lining the RNA binding cleft across subdomains 1 and 2. (a) Motif Ia residues, P223 and R225, interact with the ribose 2′ hydroxyl group and the phosphate backbone of ssRNA, respectively. (b) Motif IV residues, P363 and I365, interact similarly to Motif Ia residues. P363 interacts with the ribose 2′‐hydroxyl, whereas I365 interacts with the phosphate backbone of ssRNA intermediate. (c) Motif IVa residues, R387 and K388, interact with the RNA phosphate backbone. (d) Motif V residue, T408, interacts with the RNA phosphate backbone as well
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RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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