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4lq9

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==Crystal structure of human norovirus RNA-dependent RNA-polymerase in complex with NAF2==
==Crystal structure of human norovirus RNA-dependent RNA-polymerase in complex with NAF2==
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<StructureSection load='4lq9' size='340' side='right' caption='[[4lq9]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
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<StructureSection load='4lq9' size='340' side='right'caption='[[4lq9]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4lq9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Norovirus Norovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LQ9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LQ9 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4lq9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Norovirus Norovirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LQ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LQ9 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=21D:NAPHTHALENE-1,5-DISULFONIC+ACID'>21D</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.04&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lq3|4lq3]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=21D:NAPHTHALENE-1,5-DISULFONIC+ACID'>21D</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<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=4lq9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lq9 OCA], [http://pdbe.org/4lq9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lq9 RCSB], [http://www.ebi.ac.uk/pdbsum/4lq9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lq9 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lq9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lq9 OCA], [https://pdbe.org/4lq9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lq9 RCSB], [https://www.ebi.ac.uk/pdbsum/4lq9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lq9 ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q2N379_9CALI Q2N379_9CALI]
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Noroviruses are members of the Caliciviridae family of positive sense RNA viruses. In humans Noroviruses cause rapid onset diarrhea and vomiting. Currently Norovirus infection is responsible for 21 million gastroenteritis yearly cases in the USA. Nevertheless, despite the obvious public health and socio-economic relevance, no effective vaccines/antivirals are yet available to treat Norovirus infection. Since the activity of RNA-dependent RNA polymerase (RdRp) plays a key role in genome replication and in the synthesis/amplification of subgenomic RNA, the enzyme is considered a promising target for antiviral drug development. In this context, following the identification of suramin and NF023 as Norovirus RdRp inhibitors, we analyzed the potential inhibitory role of naphthalene di-sulfonate (NAF2), a fragment derived from these two molecules. Although NAF2, tested in enzymatic polymerase inhibition assays, displayed low activity against RdRp (IC50=14muM), the crystal structure of human Norovirus RdRp revealed a thumb domain NAF2 binding site that differs from that characterized for NF023/suramin. To further map the new potential inhibitory site, we focused on the structurally related molecule pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) tetrasodium salt (PPNDS). PPNDS displayed below-micromolar inhibitory activity versus human Norovirus RdRp (IC50=0.45muM), similarly to suramin and NF023. Inspection of the crystal structure of the RdRp/PPNDS complex showed that the inhibitor bound to the NAF2 thumb domain site, highlighting the relevance of such new binding site for exploiting Norovirus RdRp inhibitors.
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Naphthalene-sulfonate inhibitors of human norovirus RNA-dependent RNA-polymerase.,Tarantino D, Pezzullo M, Mastrangelo E, Croci R, Rohayem J, Robel I, Bolognesi M, Milani M Antiviral Res. 2014 Feb;102:23-8. doi: 10.1016/j.antiviral.2013.11.016. Epub 2013, Dec 4. PMID:24316032<ref>PMID:24316032</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4lq9" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[RNA polymerase|RNA polymerase]]
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*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Large Structures]]
[[Category: Norovirus]]
[[Category: Norovirus]]
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[[Category: Croci, R]]
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[[Category: Croci R]]
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[[Category: Mastrangelo, E]]
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[[Category: Mastrangelo E]]
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[[Category: Milani, M]]
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[[Category: Milani M]]
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[[Category: Tarantino, D]]
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[[Category: Tarantino D]]
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[[Category: Rdrp-inhibotir complex]]
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[[Category: Rna-dependent-rna-polymerase]]
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[[Category: Viral protein-replication inhibitor complex]]
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Current revision

Crystal structure of human norovirus RNA-dependent RNA-polymerase in complex with NAF2

PDB ID 4lq9

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