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(→Dengue Virus Non-Structural Protein NS5)
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NS5 is a 104 kDa, 900 amino acid long protein, making it the largest of the DENV proteins. NS5 is also the most conserved among the viral proteins with at least 67% sequence similarity among the four serotypes. According to structural and biochemical studies, 3 functional domains exist within NS5. These being a methyltransferase (MTase) domain which spans residues 6-262 and a RNA-dependent RNA polymerase (RdRp) domain spanning residues 273-883 connected by a flexible linker domain roughly 10 amino acids (residues 263-272) in length. GREEN LINK
NS5 is a 104 kDa, 900 amino acid long protein, making it the largest of the DENV proteins. NS5 is also the most conserved among the viral proteins with at least 67% sequence similarity among the four serotypes. According to structural and biochemical studies, 3 functional domains exist within NS5. These being a methyltransferase (MTase) domain which spans residues 6-262 and a RNA-dependent RNA polymerase (RdRp) domain spanning residues 273-883 connected by a flexible linker domain roughly 10 amino acids (residues 263-272) in length. GREEN LINK
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The RdRp is a feature unique to viruses and may be considered as a target for antiviral therapy. This domain is similar to other polymerases in that it contains finger, thumb and palm subdomains as well as making use of a common catalytic mechanism for the incorporation of nucleotides involving two metal ions (zinc in NS5) coordinated by aspartic acid residues located in the finger and thumb subdomains. Together the thumb and palm subdomain form a tunnel through which the RNA template and nucleotides enter en route to the catalytic core.
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The RdRp is a feature unique to viruses and may be considered as a target for antiviral therapy. This domain is similar to other polymerases in that it contains finger, thumb, and palm subdomains as well as making use of a common catalytic mechanism for nucleotide incorporation involving two metal ions (zinc in NS5) coordinated by ****aspartic acid**** residues located in the finger and thumb subdomains. Together, the thumb and palm subdomain form a tunnel through which the RNA template and nucleotides enter en route to the catalytic core.
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Through mutation studies in DENV4, residues K95 and R353 have been implicated in critical but non-enzymatic roles in virus RNA replication and infectivity while Y119 has been shown to be necessary for MTase activity and thus a requirement for viral replication. Because of a majority of polar interactions as well as a small inter-domain buried surface area (1502A), it has been suggested that the two enzymatic domains may be able to associate and dissociate from each other with a relatively small energy penalty. Additionally, this dynamic interaction may also lend itself to making it easy to recruit other viral and/or host proteins as part of the replication complex.
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Through mutation studies in DENV4, residues K95 and R353 have been implicated in critical but non-enzymatic roles in virus RNA replication and infectivity while Y119 has been shown to be necessary for MTase activity and thus a requirement for viral replication. Because of a majority of polar interactions as well as a small inter-domain buried surface area (1502A), it has been suggested that the two enzymatic domains may be able to associate and dissociate from each other with a relatively small energy penalty. Additionally, this dynamic interaction may also lend itself to making it easy to recruit other viral and/or host proteins as part of the replication complex.
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== Function ==
== Function ==

Revision as of 01:20, 23 April 2015

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Aedes Aegypti mosquito
Aedes Aegypti mosquito


Dengue Virus Non-Structural Protein NS5

The dengue virus (DENV) belongs to genus Flavivirus, which also includes the West Nile Virus, Japanese Encephalitis Virus and Yellow Fever Virus. Mosquito-borne DENV causes dengue fever which can then progress to dengue hemorrhagic fever and dengue shock syndrome. Endemic to the tropics and subtropics, it is mainly transmitted by Aedes mosquitoes. Although there are 390 million dengue infections reported annually, no specific antiviral drug or vaccine has been developed yet.

There are four serotypes of the virus (DENV-1 – DENV-4)whose respective genomes share 60% sequence identity, with 90% sequence identity within a serotype. The viral genome encodes three structural proteins (capsid, membrane and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). By associating with host cofactors and each other, NS proteins form multi-protein replication complexes, which comprise the viral replication machinery. The NS5 primary sequence is generally well conserved across serotypes and also shares some similarity with the NS5 protein of other flaviviruses.

[1]


[2]

Structure

DENV NS5 (4V0Q)

Cartoon view of NS5

Drag the structure with the mouse to rotate

References

  1. ↑ Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060. Epub 2013 Apr 7. PMID:23563266 doi:http://dx.doi.org/10.1038/nature12060
  2. ↑ Potisopon S, Priet S, Collet A, Decroly E, Canard B, Selisko B. The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. Nucleic Acids Res. 2014 Oct;42(18):11642-56. doi: 10.1093/nar/gku666. Epub 2014, Sep 10. PMID:25209234 doi:http://dx.doi.org/10.1093/nar/gku666
  3. ↑ Zhao Y, Soh TS, Zheng J, Chan KW, Phoo WW, Lee CC, Tay MY, Swaminathan K, Cornvik TC, Lim SP, Shi PY, Lescar J, Vasudevan SG, Luo D. A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication. PLoS Pathog. 2015 Mar 16;11(3):e1004682. doi: 10.1371/journal.ppat.1004682., eCollection 2015 Mar. PMID:25775415 doi:http://dx.doi.org/10.1371/journal.ppat.1004682
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