View source for 8pup


==Influenza A/California/07/2009(H1N1) endonuclease in complex with purpurogallin-like compound==
<StructureSection load='8pup' size='340' side='right'caption='[[8pup]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8pup]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/California/07/2009(H1N1)) Influenza A virus (A/California/07/2009(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8PUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PUP FirstGlance]. <br>
</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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=H2I:~{N}-[(4-hydroxyphenyl)methyl]-3,4,6-tris(oxidanyl)-5-oxidanylidene-benzo[7]annulene-8-carboxamide'>H2I</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></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=8pup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pup OCA], [https://pdbe.org/8pup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pup RCSB], [https://www.ebi.ac.uk/pdbsum/8pup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pup ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C3W5X6_9INFA C3W5X6_9INFA] Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity.[HAMAP-Rule:MF_04063]
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== Publication Abstract from PubMed ==
The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg(2+) and Mn(2+) ions, a small-molecule inhibitor with a metal-binding pharmacophore can halt endonuclease activity. Herein, two 3'-dehydroxypurpurogallin-4-carboxamide series, namely twelve C-4' unsubstituted and twelve C-4' phenyl substituted congeners were designed and prepared to be tested as inhibitors of the metal-dependent viral enzyme. These inhibitors were accessed through the chemoenzymatic reaction of gallic acid with either pyrocatechol or phenylpyrocatechol moderated by laccase, followed by amidation. Experimental IC(50) values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC(50) values around 0.35 muM. Using X-ray crystallography, we analyzed structure of the endonuclease in complex with one potent 3'-dehydroxypurpurogallin-carboxamide at 2.0 A resolution, revealing the coordination of the compound's triad of oxygen atoms with the two metal ions in the influenza A endonuclease active site.

3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex.,Kral M, Kotacka T, Reiberger R, Panyrkova G, Radilova K, Osifova Z, Flieger M, Konvalinka J, Majer P, Kozisek M, Machara A ChemMedChem. 2024 Oct 14:e202400577. doi: 10.1002/cmdc.202400577. PMID:39400442<ref>PMID:39400442</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8pup" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Kotacka T]]
[[Category: Radilova K]]