| Structural highlights
Function
POLG_KUNJM Capsid protein C self-assembles to form an icosahedral capsid about 30 nm in diameter. The capsid encapsulates the genomic RNA (By similarity).[1] [2] [3] [4] prM acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated (By similarity).[5] [6] [7] [8] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[9] [10] [11] [12] Non-structural protein 1 is involved in virus replication and regulation of the innate immune response (By similarity).[13] [14] [15] [16] Non-structural protein 2A may be involved viral RNA replication and capsid assembly (Potential).[17] [18] [19] [20] Non-structural protein 2B is a required cofactor for the serine protease function of NS3 (By similarity).[21] [22] [23] [24] Serine protease NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity).[25] [26] [27] [28] Non-structural protein 4A induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the NS3 helicase (By similarity).[29] [30] [31] [32] Peptide 2k functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter (By similarity).[33] [34] [35] [36] Non-structural protein 4B inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway (By similarity).[37] [38] [39] [40] RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome, and performs the capping of genomes in the cytoplasm. NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Besides its role in genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host JAK1 and TYK2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway.[41] [42] [43] [44]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Viruses of the family Flaviviridae are important human and animal pathogens. Among them, the Flaviviruses dengue (DENV) and West Nile (WNV) cause regular outbreaks with fatal outcomes. The RNA-dependent RNA polymerase (RdRp) activity of the non-structural protein 5 (NS5) is a key activity for viral RNA replication. In this study, crystal structures of enzymatically active and inactive WNV RdRp domains were determined at 3.0- and 2.35-A resolution, respectively. The determined structures were shown to be mostly similar to the RdRps of the Flaviviridae members hepatitis C and bovine viral diarrhea virus, although with unique elements characteristic for the WNV RdRp. Using a reverse genetic system, residues involved in putative interactions between the RNA-cap methyltransferase (MTase) and the RdRp domain of Flavivirus NS5 were identified. This allowed us to propose a model for the structure of the full-length WNV NS5 by in silico docking of the WNV MTase domain (modeled from our previously determined structure of the DENV MTase domain) onto the RdRp domain. The Flavivirus RdRp domain structure determined here should facilitate both the design of anti-Flavivirus drugs and structure-function studies of the Flavivirus replication complex in which the multifunctional NS5 protein plays a central role.
Crystal structure of the RNA polymerase domain of the West Nile virus non-structural protein 5.,Malet H, Egloff MP, Selisko B, Butcher RE, Wright PJ, Roberts M, Gruez A, Sulzenbacher G, Vonrhein C, Bricogne G, Mackenzie JM, Khromykh AA, Davidson AD, Canard B J Biol Chem. 2007 Apr 6;282(14):10678-89. Epub 2007 Feb 7. PMID:17287213[45]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. J Virol. 2008 May;82(10):4731-41. doi: 10.1128/JVI.00002-08. Epub 2008 Mar 12. PMID:18337583 doi:10.1128/JVI.00002-08
- ↑ Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010 Oct;84(20):10438-47. doi: 10.1128/JVI.00986-10. Epub 2010 Aug 4. PMID:20686019 doi:10.1128/JVI.00986-10
- ↑ Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005 Feb;79(3):1343-50. PMID:15650160 doi:10.1128/JVI.79.3.1343-1350.2005
- ↑ Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, Garcia-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15. doi: 10.1128/JVI.01161-09. Epub 2010 Jan 27. PMID:20106931 doi:10.1128/JVI.01161-09
- ↑ Malet H, Egloff MP, Selisko B, Butcher RE, Wright PJ, Roberts M, Gruez A, Sulzenbacher G, Vonrhein C, Bricogne G, Mackenzie JM, Khromykh AA, Davidson AD, Canard B. Crystal structure of the RNA polymerase domain of the West Nile virus non-structural protein 5. J Biol Chem. 2007 Apr 6;282(14):10678-89. Epub 2007 Feb 7. PMID:17287213 doi:10.1074/jbc.M607273200
|
