Sandbox Reserved 1088: Difference between revisions
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{{UniHelsinki_ProteinCourse_2015}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | {{UniHelsinki_ProteinCourse_2015}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
<StructureSection load='4V0Q' size='340' side='right' caption='Cartoon view of NS5 (PDB ID: 4V0Q)' scene=''> | |||
== Dengue Virus Non-Structural Protein NS5 == | == Dengue Virus Non-Structural Protein NS5 == | ||
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[[Image:Aedes aegypti.jpg|right|200px|thumb|''Aedes aegypti'' mosquito]] | [[Image:Aedes aegypti.jpg|right|200px|thumb|''Aedes aegypti'' mosquito]] | ||
The dengue virus (DENV) belongs to genus ''Flavivirus'', which also includes the West Nile Virus, Japanese Encephalitis Virus and Yellow Fever Virus. As a mosquito-borne pathogen, DENV causes dengue fever which can progress to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). 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 | The dengue virus (DENV) belongs to genus ''Flavivirus'', which also includes the West Nile Virus, Japanese Encephalitis Virus and Yellow Fever Virus. As a mosquito-borne pathogen, DENV causes dengue fever which can progress to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). 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 yet developed <ref name= "Bhatt">PMID:23563266</ref>. | ||
Dengue fever manifests as a combination of severe headache, chills, backache and joint pain. DHF is a potentially deadly form of the fever characterized by sudden increase in body temperature and impaired blood homeostasis and clotting. DSS involves further impairment due to blood loss. Dengue virus can inhibit various mediators of the innate immune system such as interferons and bypass the inflammatory response<ref name= "Mangold">PMID:23640151</ref>. | Dengue fever manifests as a combination of severe headache, chills, backache and joint pain. DHF is a potentially deadly form of the fever characterized by sudden increase in body temperature and impaired blood homeostasis and clotting. DSS involves further impairment due to blood loss. Dengue virus can inhibit various mediators of the innate immune system such as interferons and bypass the inflammatory response<ref name= "Mangold">PMID:23640151</ref>. | ||
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== Structure & Function == | == Structure & Function == | ||
[[Image:NS5.JPG|left|200px|thumb|Overall structure of DENV NS5 highlighting functional domains and key inter-domain interactions]] | |||
NS5 is a 104 kDa, 900 amino acids long protein, making it the largest of the DENV proteins. As per structural and biochemical studies, two functional domains exist within NS5. These being a S-adenosyl-L-methionine (SAM)-dependent methyltransferase (MTase) domain which spans residues 6-262 and a RNA-dependent RNA polymerase (RdRp) domain spanning residues 273-883 that are connected to each other by a flexible linker 10 amino acids in length (residues 263-272)<ref name= "Zhao"/>. | |||
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== Methyltransferase domain == | == Methyltransferase domain == | ||
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Together, the thumb and finger subdomains form a <scene name='70/700001/4v0q_rdrpp/1'>tunnel</scene> through which the RNA template and nucleotides enter en route to the catalytic core within the palm subdomain. Inside the tunnel, a priming loop protrudes from a thumb subdomain towards the active site where it controls access to and exit into the catalytic core and is thus critical in ''de novo'' initiation<ref name= "Yap"/><ref name= "Wu"/>. The RdRp is a feature unique to viruses and may be considered as a target for antiviral therapy. | Together, the thumb and finger subdomains form a <scene name='70/700001/4v0q_rdrpp/1'>tunnel</scene> through which the RNA template and nucleotides enter en route to the catalytic core within the palm subdomain. Inside the tunnel, a priming loop protrudes from a thumb subdomain towards the active site where it controls access to and exit into the catalytic core and is thus critical in ''de novo'' initiation<ref name= "Yap"/><ref name= "Wu"/>. The RdRp is a feature unique to viruses and may be considered as a target for antiviral therapy. | ||
The <scene name='70/700001/4v0q_linker/1'>linker</scene> | == Linker region== | ||
The <scene name='70/700001/4v0q_linker/1'>linker region </scene> defines the boundaries between the MTase and RdRp domains. It connects the two enzymatic domains acting like a swivel allowing the domains to adopt various orientations relative to each other. Residues 263-266, located after the MTase C-terminus, are key in this regard. They fold into a short 3<sub>10</sub> helix (though other conformations are also thought possible) resulting in compaction or elongation of the polypeptide chain and allowing for various inter-domain interactions over the course of the viral life cycle<ref name= "Zhao"/>. Apart from this flexibility, it has been demonstrated that the linker residues (268-272) N-terminal to the RdRp region enhance stability and polymerase activity as evidenced by results showing superior RdRp activity when the linker was present as compared to the RdRp alone, further corroborating that inter-domain interactions are required to successfully carry out RNA synthesis and viral replication and hence maintain infectivity<ref name= "Wu">PMID:25320292</ref><ref name= "Zhao"/><ref name= "Potisopon">PMID:25209234</ref>. | |||
[[Image:Linker.png|center|400px|thumb|Residues of the linker region]] | [[Image:Linker.png|center|400px|thumb|Residues of the linker region]] | ||
