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<StructureSection load='4cbg' size='340' side='right'caption='[[4cbg]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
<StructureSection load='4cbg' size='340' side='right'caption='[[4cbg]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4cbg]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Classical_swine_fever_virus Classical swine fever virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CBG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CBG FirstGlance]. <br>
<table><tr><td colspan='2'>[[4cbg]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Classical_swine_fever_virus Classical swine fever virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CBG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CBG FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.82&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cbh|4cbh]], [[4cbi|4cbi]], [[4cbl|4cbl]], [[4cbm|4cbm]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4cbg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbg OCA], [https://pdbe.org/4cbg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cbg RCSB], [https://www.ebi.ac.uk/pdbsum/4cbg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbg ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cbg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbg OCA], [http://pdbe.org/4cbg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cbg RCSB], [http://www.ebi.ac.uk/pdbsum/4cbg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbg ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/POLG_CSFVA POLG_CSFVA]] E(rns), E1 and E2 are responsible of cell attachment and subsequent fusion of viral and cellular membrane. P7 forms a leader sequence to properly orient NS2 in the membrane. Uncleaved NS2-3 is required for production of infectious virus. NS2 protease seems to play a vital role in viral RNA replication control and in the pathogenicity of the virus.[PROSITE-ProRule:PRU01029]  NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS4A is a cofactor for the NS3 protease activity. RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome.[PROSITE-ProRule:PRU00539]  
[https://www.uniprot.org/uniprot/POLG_CSFAT POLG_CSFAT] Leader cysteine autoprotease that cleaves itself from the nascent polyprotein during translation of the viral mRNA. Once released, plays a role in the inhibition of host innate immune response by interacting with host IRF3 and inducing its proteasomal degradation.<ref>PMID:17215286</ref> <ref>PMID:19540847</ref> <ref>PMID:24606708</ref> <ref>PMID:27334592</ref>  Packages viral RNA to form a viral nucleocapsid and thereby protects viral RNA. Also plays a role in transcription regulation. Protects the incoming virus against IFN-induced effectors.<ref>PMID:28290554</ref> <ref>PMID:9617770</ref>  Plays a role in viral entry. Interacts with host RPSA that acts as a cellular attachment receptor for the virus. Possesses also intrinsic ribonuclease (RNase) activity that can inhibit the production of type I interferon and assist in the development of persistent infections. Cleaves preferentially NpU bonds (PubMed:15113930).<ref>PMID:15113930</ref> <ref>PMID:19264773</ref> <ref>PMID:19767841</ref> <ref>PMID:25694590</ref> <ref>PMID:29235980</ref> <ref>PMID:8356450</ref>  Plays a role in cell attachment and subsequent fusion of viral and cellular membranes. Therefore, mediates together with envelope glycoprotein E2 the viral entry.<ref>PMID:15527858</ref>  Plays a role in cell attachment and subsequent fusion of viral and cellular membranes (PubMed:15527858). Therefore, mediates together with envelope glycoprotein E1 the viral entry (PubMed:15527858). Binds to host ADAM17 receptor for entry (PubMed:33684175).<ref>PMID:15527858</ref> <ref>PMID:33684175</ref>  Plays an essential role in the virus replication cycle by acting as a viroporin. Forms ion conductive pores, which alters the cell permeability allowing the transport of ions and other small molecules.<ref>PMID:22496228</ref> <ref>PMID:24189547</ref>  Autoprotease that associates with the host chaperone JIV and cleaves the NS2-3 protein between NS2 and NS3. Also plays a role in the formation of infectious particles.<ref>PMID:17482232</ref>  Plays a role in the regulation of viral RNA replication.<ref>PMID:10438869</ref>  Multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and viral genome replication. The chymotrypsin-like serine protease activity utilizes NS4A as an essential cofactor and catalyzes the cleavage of the polyprotein leading to the release of NS4A, NS4B, NS5A, and NS5B. Plays a role in the inhibition of host NF-kappa-B activation by interacting with and inhibiting host TRAF6. Interacts with NS5B to enhance RNA-dependent RNA polymerase activity.<ref>PMID:19185595</ref> <ref>PMID:28751780</ref>  Acts as a cofactor for the NS3 protease activity.<ref>PMID:17482232</ref>  Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (By similarity). Antagonizes host cell apoptosis by interacting with host ferritin heavy chain. The ORF4 protein physically binds host FTH1/FHC, resulting in the reduction of FTH1 protein levels in host cells. Reduction of FTH1 concentration further inhibits the accumulation of reactive oxygen in host cells, leading to reduced apoptosis (By similarity) (PubMed:29844394).[UniProtKB:O56125][UniProtKB:Q9Q6P4]<ref>PMID:29844394</ref>  Regulates viral RNA replication by interacting with the 3'-untranslated region of viral RNA in a dose-dependent manner. At small concentrations promotes viral synthesis by interacting with the polymerase NS5B while at large concentrations, inhibits replication.<ref>PMID:22261205</ref> <ref>PMID:22795973</ref>  Replicates the viral (+) and (-) genome.[PROSITE-ProRule:PRU00539]
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 4cbg" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4cbg" style="background-color:#fffaf0;"></div>
==See Also==
*[[Helicase 3D structures|Helicase 3D structures]]
*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]]
== References ==
== References ==
<references/>
<references/>
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[[Category: Classical swine fever virus]]
[[Category: Classical swine fever virus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bricogne, G]]
[[Category: Bricogne G]]
[[Category: Duquerroy, S]]
[[Category: Duquerroy S]]
[[Category: Kwok, J]]
[[Category: Kwok J]]
[[Category: Lamp, B]]
[[Category: Lamp B]]
[[Category: Perez, J]]
[[Category: Perez J]]
[[Category: Rey, F A]]
[[Category: Rey FA]]
[[Category: Rumenapf, T]]
[[Category: Rumenapf T]]
[[Category: Tortorici, M A]]
[[Category: Tortorici MA]]
[[Category: Vachette, P]]
[[Category: Vachette P]]
[[Category: Vonrhein, C]]
[[Category: Vonrhein C]]
[[Category: Flaviviridae ns3]]
[[Category: Hydrolase]]
[[Category: Sax]]

Latest revision as of 11:17, 9 October 2024

Pestivirus NS3 helicasePestivirus NS3 helicase

Structural highlights

4cbg is a 4 chain structure with sequence from Classical swine fever virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.82Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLG_CSFAT Leader cysteine autoprotease that cleaves itself from the nascent polyprotein during translation of the viral mRNA. Once released, plays a role in the inhibition of host innate immune response by interacting with host IRF3 and inducing its proteasomal degradation.[1] [2] [3] [4] Packages viral RNA to form a viral nucleocapsid and thereby protects viral RNA. Also plays a role in transcription regulation. Protects the incoming virus against IFN-induced effectors.[5] [6] Plays a role in viral entry. Interacts with host RPSA that acts as a cellular attachment receptor for the virus. Possesses also intrinsic ribonuclease (RNase) activity that can inhibit the production of type I interferon and assist in the development of persistent infections. Cleaves preferentially NpU bonds (PubMed:15113930).[7] [8] [9] [10] [11] [12] Plays a role in cell attachment and subsequent fusion of viral and cellular membranes. Therefore, mediates together with envelope glycoprotein E2 the viral entry.[13] Plays a role in cell attachment and subsequent fusion of viral and cellular membranes (PubMed:15527858). Therefore, mediates together with envelope glycoprotein E1 the viral entry (PubMed:15527858). Binds to host ADAM17 receptor for entry (PubMed:33684175).[14] [15] Plays an essential role in the virus replication cycle by acting as a viroporin. Forms ion conductive pores, which alters the cell permeability allowing the transport of ions and other small molecules.[16] [17] Autoprotease that associates with the host chaperone JIV and cleaves the NS2-3 protein between NS2 and NS3. Also plays a role in the formation of infectious particles.[18] Plays a role in the regulation of viral RNA replication.[19] Multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and viral genome replication. The chymotrypsin-like serine protease activity utilizes NS4A as an essential cofactor and catalyzes the cleavage of the polyprotein leading to the release of NS4A, NS4B, NS5A, and NS5B. Plays a role in the inhibition of host NF-kappa-B activation by interacting with and inhibiting host TRAF6. Interacts with NS5B to enhance RNA-dependent RNA polymerase activity.[20] [21] Acts as a cofactor for the NS3 protease activity.[22] Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (By similarity). Antagonizes host cell apoptosis by interacting with host ferritin heavy chain. The ORF4 protein physically binds host FTH1/FHC, resulting in the reduction of FTH1 protein levels in host cells. Reduction of FTH1 concentration further inhibits the accumulation of reactive oxygen in host cells, leading to reduced apoptosis (By similarity) (PubMed:29844394).[UniProtKB:O56125][UniProtKB:Q9Q6P4][23] Regulates viral RNA replication by interacting with the 3'-untranslated region of viral RNA in a dose-dependent manner. At small concentrations promotes viral synthesis by interacting with the polymerase NS5B while at large concentrations, inhibits replication.[24] [25] Replicates the viral (+) and (-) genome.[PROSITE-ProRule:PRU00539]

Publication Abstract from PubMed

Pestiviruses form a genus in the Flaviviridae family of small enveloped viruses with a positive-sense single-stranded RNA genome. Viral replication in this family requires the activity of a superfamily 2 RNA helicase contained in the C-terminal domain of the non-structural protein 3 (NS3). NS3 features two conserved RecA-like domains (D1 and D2) with ATPase activity, plus a third domain (D3) that is important for unwinding nucleic acid duplexes. We report here the X-ray structure of the pestivirus NS3 helicase domain (pNS3h) at 2.5 A resolution. The structure deviates significantly from that of NS3 of other genera in the Flaviviridae family in D3, which contains two important insertions that result in a narrower nucleic acid binding groove. We also show that mutations in pNS3h that rescue viruses with deleted core protein map to D3, suggesting that this domain may be involved in interactions that facilitate particle assembly. Finally, structural comparisons of the enzyme in different crystalline environments, together with small angle X-ray scattering studies in solution, show that D2 is mobile with respect to the rest of the enzyme, oscillating between closed and open conformations. Binding of a non-hydrolyzable ATP analog locks pNS3h in a conformation that is more compact than the closest apo-form in our crystals. Together, our results provide new insight and bring up new questions about pNS3h function during pestivirus replication. IMPORTANCE: Although pestivirus infections impose an important toll on the livestock industry worldwide, little information is available about the non-structural proteins essential for viral replication, such as the NS3 helicase. We provide here a comparative structural and functional analysis of pNS3h with respect to its orthologs in other viruses of the same family, the flaviviruses and the hepatitis C virus. Our studies reveal differences in the nucleic acid binding groove that could have implications for understanding the unwinding specificity of pNS3h, which is only active on RNA duplexes. We also show that pNS3h has a highly dynamic behavior - a characteristic probably shared with NS3 helicases from all Flaviviridae members - that could be targeted for drug design by using recent algorithms to specifically block molecular motion. Compounds that lock the enzyme in a single conformation, or limit its dynamic range of conformations are indeed likely to block its helicase function.

X-ray structure of the pestivirus NS3 helicase and its conformation in solution.,Tortorici MA, Duquerroy S, Kwok J, Vonrhein C, Perez J, Lamp B, Bricogne G, Rumenapf T, Vachette P, Rey FA J Virol. 2015 Feb 4. pii: JVI.03165-14. PMID:25653438[26]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Bauhofer O, Summerfield A, Sakoda Y, Tratschin JD, Hofmann MA, Ruggli N. Classical swine fever virus Npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation. J Virol. 2007 Apr;81(7):3087-96. PMID:17215286 doi:10.1128/JVI.02032-06
  2. ↑ Szymanski MR, Fiebach AR, Tratschin JD, Gut M, Ramanujam VM, Gottipati K, Patel P, Ye M, Ruggli N, Choi KH. Zinc binding in pestivirus N(pro) is required for interferon regulatory factor 3 interaction and degradation. J Mol Biol. 2009 Aug 14;391(2):438-49. PMID:19540847 doi:10.1016/j.jmb.2009.06.040
  3. ↑ Gottipati K, Acholi S, Ruggli N, Choi KH. Autocatalytic activity and substrate specificity of the pestivirus N-terminal protease Npro. Virology. 2014 Mar;452-453:303-9. PMID:24606708 doi:10.1016/j.virol.2014.01.026
  4. ↑ Gottipati K, Holthauzen LM, Ruggli N, Choi KH. Pestivirus Npro Directly Interacts with Interferon Regulatory Factor 3 Monomer and Dimer. J Virol. 2016 Aug 12;90(17):7740-7. PMID:27334592 doi:10.1128/JVI.00318-16
  5. ↑ Riedel C, Lamp B, Hagen B, Indik S, Rümenapf T. The core protein of a pestivirus protects the incoming virus against IFN-induced effectors. Sci Rep. 2017 Mar 14;7:44459. PMID:28290554 doi:10.1038/srep44459
  6. ↑ Liu JJ, Wong ML, Chang TJ. The recombinant nucleocapsid protein of classical swine fever virus can act as a transcriptional regulator. Virus Res. 1998 Jan;53(1):75-80. PMID:9617770 doi:10.1016/s0168-1702(97)00132-9
  7. ↑ Hausmann Y, Roman-Sosa G, Thiel HJ, Rümenapf T. Classical swine fever virus glycoprotein E rns is an endoribonuclease with an unusual base specificity. J Virol. 2004 May;78(10):5507-12. PMID:15113930 doi:10.1128/jvi.78.10.5507-5512.2004
  8. ↑ Tews BA, Schürmann EM, Meyers G. Mutation of cysteine 171 of pestivirus E rns RNase prevents homodimer formation and leads to attenuation of classical swine fever virus. J Virol. 2009 May;83(10):4823-34. PMID:19264773 doi:10.1128/JVI.01710-08
  9. ↑ Luo X, Ling D, Li T, Wan C, Zhang C, Pan Z. Classical swine fever virus Erns glycoprotein antagonizes induction of interferon-beta by double-stranded RNA. Can J Microbiol. 2009 Jun;55(6):698-704. PMID:19767841 doi:10.1139/w09-013
  10. ↑ Chen J, He WR, Shen L, Dong H, Yu J, Wang X, Yu S, Li Y, Li S, Luo Y, Sun Y, Qiu HJ. The laminin receptor is a cellular attachment receptor for classical Swine Fever virus. J Virol. 2015 May;89(9):4894-906. PMID:25694590 doi:10.1128/JVI.00019-15
  11. ↑ Tucakov AK, Yavuz S, Schürmann EM, Mischler M, Klingebeil A, Meyers G. Restoration of glycoprotein E(rns) dimerization via pseudoreversion partially restores virulence of classical swine fever virus. J Gen Virol. 2018 Jan;99(1):86-96. PMID:29235980 doi:10.1099/jgv.0.000990
  12. ↑ Schneider R, Unger G, Stark R, Schneider-Scherzer E, Thiel HJ. Identification of a structural glycoprotein of an RNA virus as a ribonuclease. Science. 1993 Aug 27;261(5125):1169-71. PMID:8356450 doi:10.1126/science.8356450
  13. ↑ Wang Z, Nie Y, Wang P, Ding M, Deng H. Characterization of classical swine fever virus entry by using pseudotyped viruses: E1 and E2 are sufficient to mediate viral entry. Virology. 2004 Dec 5;330(1):332-41. PMID:15527858 doi:10.1016/j.virol.2004.09.023
  14. ↑ Wang Z, Nie Y, Wang P, Ding M, Deng H. Characterization of classical swine fever virus entry by using pseudotyped viruses: E1 and E2 are sufficient to mediate viral entry. Virology. 2004 Dec 5;330(1):332-41. PMID:15527858 doi:10.1016/j.virol.2004.09.023
  15. ↑ Yuan F, Li D, Li C, Zhang Y, Song H, Li S, Deng H, Gao GF, Zheng A. ADAM17 is an essential attachment factor for classical swine fever virus. PLoS Pathog. 2021 Mar 8;17(3):e1009393. PMID:33684175 doi:10.1371/journal.ppat.1009393
  16. ↑ Gladue DP, Holinka LG, Largo E, Fernandez Sainz I, Carrillo C, O'Donnell V, Baker-Branstetter R, Lu Z, Ambroggio X, Risatti GR, Nieva JL, Borca MV. Classical swine fever virus p7 protein is a viroporin involved in virulence in swine. J Virol. 2012 Jun;86(12):6778-91. PMID:22496228 doi:10.1128/JVI.00560-12
  17. ↑ Largo E, Gladue DP, Huarte N, Borca MV, Nieva JL. Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function. Antiviral Res. 2014 Jan;101:30-6. PMID:24189547 doi:10.1016/j.antiviral.2013.10.015
  18. ↑ Moulin HR, Seuberlich T, Bauhofer O, Bennett LC, Tratschin JD, Hofmann MA, Ruggli N. Nonstructural proteins NS2-3 and NS4A of classical swine fever virus: essential features for infectious particle formation. Virology. 2007 Sep 1;365(2):376-89. PMID:17482232 doi:10.1016/j.virol.2007.03.056
  19. ↑ Moser C, Stettler P, Tratschin JD, Hofmann MA. Cytopathogenic and noncytopathogenic RNA replicons of classical swine fever virus. J Virol. 1999 Sep;73(9):7787-94. PMID:10438869 doi:10.1128/JVI.73.9.7787-7794.1999
  20. ↑ Wen G, Xue J, Shen Y, Zhang C, Pan Z. Characterization of classical swine fever virus (CSFV) nonstructural protein 3 (NS3) helicase activity and its modulation by CSFV RNA-dependent RNA polymerase. Virus Res. 2009 Apr;141(1):63-70. PMID:19185595 doi:10.1016/j.virusres.2008.12.014
  21. ↑ Lv H, Dong W, Cao Z, Li X, Wang J, Qian G, Lv Q, Wang C, Guo K, Zhang Y. TRAF6 is a novel NS3-interacting protein that inhibits classical swine fever virus replication. Sci Rep. 2017 Jul 27;7(1):6737. PMID:28751780 doi:10.1038/s41598-017-06934-1
  22. ↑ Moulin HR, Seuberlich T, Bauhofer O, Bennett LC, Tratschin JD, Hofmann MA, Ruggli N. Nonstructural proteins NS2-3 and NS4A of classical swine fever virus: essential features for infectious particle formation. Virology. 2007 Sep 1;365(2):376-89. PMID:17482232 doi:10.1016/j.virol.2007.03.056
  23. ↑ Qian G, Lv H, Lin J, Li X, Lv Q, Wang T, Zhang J, Dong W, Guo K, Zhang Y. FHC, an NS4B-interacting Protein, Enhances Classical Swine Fever Virus Propagation and Acts Positively in Viral Anti-apoptosis. Sci Rep. 2018 May 29;8(1):8318. PMID:29844394 doi:10.1038/s41598-018-26777-8
  24. ↑ Sheng C, Chen Y, Xiao J, Xiao J, Wang J, Li G, Chen J, Xiao M. Classical swine fever virus NS5A protein interacts with 3'-untranslated region and regulates viral RNA synthesis. Virus Res. 2012 Feb;163(2):636-43. PMID:22261205 doi:10.1016/j.virusres.2012.01.004
  25. ↑ Chen Y, Xiao J, Xiao J, Sheng C, Wang J, Jia L, Zhi Y, Li G, Chen J, Xiao M. Classical swine fever virus NS5A regulates viral RNA replication through binding to NS5B and 3'UTR. Virology. 2012 Oct 25;432(2):376-88. PMID:22795973 doi:10.1016/j.virol.2012.04.014
  26. ↑ Tortorici MA, Duquerroy S, Kwok J, Vonrhein C, Perez J, Lamp B, Bricogne G, Rumenapf T, Vachette P, Rey FA. X-ray structure of the pestivirus NS3 helicase and its conformation in solution. J Virol. 2015 Feb 4. pii: JVI.03165-14. PMID:25653438 doi:http://dx.doi.org/10.1128/JVI.03165-14

4cbg, resolution 2.82Å

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