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| - | {{Seed}} | |
| - | [[Image:3l29.jpg|left|200px]] | |
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| - | <!-- | + | ==Crystal Structure of Zaire Ebola VP35 interferon inhibitory domain K319A/R322A mutant== |
| - | The line below this paragraph, containing "STRUCTURE_3l29", creates the "Structure Box" on the page.
| + | <StructureSection load='3l29' size='340' side='right'caption='[[3l29]], [[Resolution|resolution]] 1.70Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3l29]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Ebola_virus_-_Mayinga,_Zaire,_1976 Ebola virus - Mayinga, Zaire, 1976]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3L29 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3L29 FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | {{STRUCTURE_3l29| PDB=3l29 | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3l29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l29 OCA], [https://pdbe.org/3l29 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3l29 RCSB], [https://www.ebi.ac.uk/pdbsum/3l29 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3l29 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/VP35_EBOZM VP35_EBOZM] Acsts as a polymerase cofactor in the RNA polymerase transcription and replication complex. Prevents establishment of cellular antiviral state by blocking virus-induced phosphorylation and activation of interferon regulatory factor 3 (IRF3), a transcription factor critical for the induction of interferons alpha and beta. The mechanism by which this blockage occurs remains incompletely defined, a hypothesis suggests that VP35 dsRNA-binding activity prevents activation of IRF3 by sequestering dsRNA. Also inhibits the antiviral effect mediated by the interferon-induced, double-stranded RNA-activated protein kinase EIF2AK2/PKR.<ref>PMID:9971816</ref> <ref>PMID:11027311</ref> <ref>PMID:12829834</ref> <ref>PMID:16495261</ref> <ref>PMID:17065211</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-alpha/beta responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-alpha/beta production were identified. Solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography reveal minimal structural perturbations in the K319A/R322A VP35 double mutant and suggest that loss of basic charge leads to altered function. Recombinant EBOVs encoding the mutant VP35 exhibit, relative to wild-type VP35 viruses, minimal growth attenuation in IFN-defective Vero cells but severe impairment in IFN-competent cells. In guinea pigs, the VP35 mutant virus revealed a complete loss of virulence. Strikingly, the VP35 mutant virus effectively immunized animals against subsequent wild-type EBOV challenge. These in vivo studies, using recombinant EBOV viruses, combined with the accompanying biochemical and structural analyses directly correlate VP35 dsRNA binding and IFN inhibition functions with viral pathogenesis. Moreover, these studies provide a framework for the development of antivirals targeting this critical EBOV virulence factor. |
| | | | |
| - | ===Crystal Structure of Zaire Ebola VP35 interferon inhibitory domain K319A/R322A mutant===
| + | Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs.,Prins KC, Delpeut S, Leung DW, Reynard O, Volchkova VA, Reid SP, Ramanan P, Cardenas WB, Amarasinghe GK, Volchkov VE, Basler CF J Virol. 2010 Mar;84(6):3004-15. Epub 2010 Jan 13. PMID:20071589<ref>PMID:20071589</ref> |
| | | | |
| - | | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | <!--
| + | </div> |
| - | The line below this paragraph, {{ABSTRACT_PUBMED_20071589}}, adds the Publication Abstract to the page
| + | <div class="pdbe-citations 3l29" style="background-color:#fffaf0;"></div> |
| - | (as it appears on PubMed at http://www.pubmed.gov), where 20071589 is the PubMed ID number.
| + | == References == |
| - | -->
| + | <references/> |
| - | {{ABSTRACT_PUBMED_20071589}}
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==About this Structure== | + | [[Category: Ebola virus - Mayinga, Zaire, 1976]] |
| - | 3L29 is a 2 chains structure with sequences from [http://en.wikipedia.org/wiki/Zaire_ebolavirus Zaire ebolavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3L29 OCA].
| + | [[Category: Large Structures]] |
| - | | + | [[Category: Amarasinghe GK]] |
| - | ==Reference== | + | [[Category: Borek DM]] |
| - | <ref group="xtra">PMID:20071589</ref><references group="xtra"/> | + | [[Category: Leung DW]] |
| - | [[Category: Zaire ebolavirus]] | + | [[Category: Ramanan P]] |
| - | [[Category: Amarasinghe, G K.]]
| + | |
| - | [[Category: Borek, D M.]] | + | |
| - | [[Category: Leung, D W.]] | + | |
| - | [[Category: Ramanan, P.]] | + | |
| - | [[Category: Coiled coil]] | + | |
| - | [[Category: Host cytoplasm]] | + | |
| - | [[Category: Interferon antiviral evasion]]
| + | |
| - | [[Category: Interferon antiviral system evasion]]
| + | |
| - | [[Category: Rna binding domain]]
| + | |
| - | [[Category: Rna binding protein]]
| + | |
| - | [[Category: Rna replication]]
| + | |
| - | [[Category: Rna-binding]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Virion]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 3 09:41:14 2010''
| + | |
| Structural highlights
Function
VP35_EBOZM Acsts as a polymerase cofactor in the RNA polymerase transcription and replication complex. Prevents establishment of cellular antiviral state by blocking virus-induced phosphorylation and activation of interferon regulatory factor 3 (IRF3), a transcription factor critical for the induction of interferons alpha and beta. The mechanism by which this blockage occurs remains incompletely defined, a hypothesis suggests that VP35 dsRNA-binding activity prevents activation of IRF3 by sequestering dsRNA. Also inhibits the antiviral effect mediated by the interferon-induced, double-stranded RNA-activated protein kinase EIF2AK2/PKR.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-alpha/beta responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-alpha/beta production were identified. Solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography reveal minimal structural perturbations in the K319A/R322A VP35 double mutant and suggest that loss of basic charge leads to altered function. Recombinant EBOVs encoding the mutant VP35 exhibit, relative to wild-type VP35 viruses, minimal growth attenuation in IFN-defective Vero cells but severe impairment in IFN-competent cells. In guinea pigs, the VP35 mutant virus revealed a complete loss of virulence. Strikingly, the VP35 mutant virus effectively immunized animals against subsequent wild-type EBOV challenge. These in vivo studies, using recombinant EBOV viruses, combined with the accompanying biochemical and structural analyses directly correlate VP35 dsRNA binding and IFN inhibition functions with viral pathogenesis. Moreover, these studies provide a framework for the development of antivirals targeting this critical EBOV virulence factor.
Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs.,Prins KC, Delpeut S, Leung DW, Reynard O, Volchkova VA, Reid SP, Ramanan P, Cardenas WB, Amarasinghe GK, Volchkov VE, Basler CF J Virol. 2010 Mar;84(6):3004-15. Epub 2010 Jan 13. PMID:20071589[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Muhlberger E, Weik M, Volchkov VE, Klenk HD, Becker S. Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J Virol. 1999 Mar;73(3):2333-42. PMID:9971816
- ↑ Basler CF, Wang X, Muhlberger E, Volchkov V, Paragas J, Klenk HD, Garcia-Sastre A, Palese P. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12289-94. PMID:11027311 doi:10.1073/pnas.220398297
- ↑ Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Muhlberger E, Bray M, Klenk HD, Palese P, Garcia-Sastre A. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J Virol. 2003 Jul;77(14):7945-56. PMID:12829834
- ↑ Enterlein S, Warfield KL, Swenson DL, Stein DA, Smith JL, Gamble CS, Kroeker AD, Iversen PL, Bavari S, Muhlberger E. VP35 knockdown inhibits Ebola virus amplification and protects against lethal infection in mice. Antimicrob Agents Chemother. 2006 Mar;50(3):984-93. PMID:16495261 doi:10.1128/AAC.50.3.984-993.2006
- ↑ Feng Z, Cerveny M, Yan Z, He B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J Virol. 2007 Jan;81(1):182-92. Epub 2006 Oct 25. PMID:17065211 doi:JVI.01006-06
- ↑ Prins KC, Delpeut S, Leung DW, Reynard O, Volchkova VA, Reid SP, Ramanan P, Cardenas WB, Amarasinghe GK, Volchkov VE, Basler CF. Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs. J Virol. 2010 Mar;84(6):3004-15. Epub 2010 Jan 13. PMID:20071589 doi:10.1128/JVI.02459-09
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