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4ibi

From Proteopedia

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Current revision

Ebola virus VP35 bound to small molecule

Structural highlights

4ibi is a 2 chain structure with sequence from Ebola virus - Mayinga, Zaire, 1976. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.473Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The Ebola virus (EBOV) genome only encodes a single viral polypeptide with enzymatic activity, the viral large (L) RNA-dependent RNA polymerase protein. However, currently, there is limited information about the L protein, which has hampered the development of antivirals. Therefore, antifiloviral therapeutic efforts must include additional targets such as protein-protein interfaces. Viral protein 35 (VP35) is multifunctional and plays important roles in viral pathogenesis, including viral mRNA synthesis and replication of the negative-sense RNA viral genome. Previous studies revealed that mutation of key basic residues within the VP35 interferon inhibitory domain (IID) results in significant EBOV attenuation, both in vitro and in vivo. In the current study, we use an experimental pipeline that includes structure-based in silico screening and biochemical and structural characterization, along with medicinal chemistry, to identify and characterize small molecules that target a binding pocket within VP35. NMR mapping experiments and high-resolution x-ray crystal structures show that select small molecules bind to a region of VP35 IID that is important for replication complex formation through interactions with the viral nucleoprotein (NP). We also tested select compounds for their ability to inhibit VP35 IID-NP interactions in vitro as well as VP35 function in a minigenome assay and EBOV replication. These results confirm the ability of compounds identified in this study to inhibit VP35-NP interactions in vitro and to impair viral replication in cell-based assays. These studies provide an initial framework to guide development of antifiloviral compounds against filoviral VP35 proteins.

In Silico Derived Small Molecules Bind the Filovirus VP35 Protein and Inhibit Its Polymerase Cofactor Activity.,Brown CS, Lee MS, Leung DW, Wang T, Xu W, Luthra P, Anantpadma M, Shabman RS, Melito LM, Macmillan KS, Borek DM, Otwinowski Z, Ramanan P, Stubbs AJ, Peterson DS, Binning JM, Tonelli M, Olson MA, Davey R, Ready JM, Basler CF, Amarasinghe GK J Mol Biol. 2014 Feb 1. pii: S0022-2836(14)00048-5. doi:, 10.1016/j.jmb.2014.01.010. PMID:24495995^[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
↑ Brown CS, Lee MS, Leung DW, Wang T, Xu W, Luthra P, Anantpadma M, Shabman RS, Melito LM, Macmillan KS, Borek DM, Otwinowski Z, Ramanan P, Stubbs AJ, Peterson DS, Binning JM, Tonelli M, Olson MA, Davey R, Ready JM, Basler CF, Amarasinghe GK. In Silico Derived Small Molecules Bind the Filovirus VP35 Protein and Inhibit Its Polymerase Cofactor Activity. J Mol Biol. 2014 Feb 1. pii: S0022-2836(14)00048-5. doi:, 10.1016/j.jmb.2014.01.010. PMID:24495995 doi:http://dx.doi.org/10.1016/j.jmb.2014.01.010

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ibi"

@@ Line 1: / Line 1: @@
 ==Ebola virus VP35 bound to small molecule==
-<StructureSection load='4ibi' size='340' side='right' caption='[[4ibi]], [[Resolution|resolution]] 1.47&Aring;' scene=''>
+<StructureSection load='4ibi' size='340' side='right'caption='[[4ibi]], [[Resolution|resolution]] 1.47&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4ibi]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ebozm Ebozm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IBI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IBI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4ibi]] 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=4IBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IBI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1D8:3-{(2S)-2-(7-CHLORO-1,3-BENZODIOXOL-5-YL)-4-HYDROXY-5-OXO-3-[3-(TRIFLUOROMETHYL)BENZOYL]-2,5-DIHYDRO-1H-PYRROL-1-YL}BENZOIC+ACID'>1D8</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]] 1.473&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ibb|4ibb]], [[4ibc|4ibc]], [[4ibd|4ibd]], [[4ibe|4ibe]], [[4ibf|4ibf]], [[4ibh|4ibh]], [[4ibj|4ibj]], [[4ibk|4ibk]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1D8:3-{(2S)-2-(7-CHLORO-1,3-BENZODIOXOL-5-YL)-4-HYDROXY-5-OXO-3-[3-(TRIFLUOROMETHYL)BENZOYL]-2,5-DIHYDRO-1H-PYRROL-1-YL}BENZOIC+ACID'>1D8</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VP35 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=128952 EBOZM])</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=4ibi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ibi OCA], [https://pdbe.org/4ibi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ibi RCSB], [https://www.ebi.ac.uk/pdbsum/4ibi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ibi 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=4ibi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ibi OCA], [http://pdbe.org/4ibi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ibi RCSB], [http://www.ebi.ac.uk/pdbsum/4ibi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ibi ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Ebozm]]
+[[Category: Ebola virus - Mayinga, Zaire, 1976]]
-[[Category: Amarasinghe, G K]]
+[[Category: Large Structures]]
-[[Category: Binning, J M]]
+[[Category: Amarasinghe GK]]
-[[Category: Borek, D M]]
+[[Category: Binning JM]]
-[[Category: Brown, C S]]
+[[Category: Borek DM]]
-[[Category: Leung, D W]]
+[[Category: Brown CS]]
-[[Category: Otwinowski, Z]]
+[[Category: Leung DW]]
-[[Category: Peterson, D S]]
+[[Category: Otwinowski Z]]
-[[Category: Ramanan, P]]
+[[Category: Peterson DS]]
-[[Category: Stubbs, A J]]
+[[Category: Ramanan P]]
-[[Category: Xu, W]]
+[[Category: Stubbs AJ]]
-[[Category: Interferon inhibitor domain]]
+[[Category: Xu W]]
-[[Category: Transcription-transcription inhibitor complex]]

4ibi

From Proteopedia

Current revision

Ebola virus VP35 bound to small molecule

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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