View source for 8t81


==Influenza PAN endonuclease E23K mutant with 6-(4-(1H-tetrazol-5-yl)-2-(trifluoromethyl)phenyl)-3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid==
<StructureSection load='8t81' size='340' side='right'caption='[[8t81]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8t81]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/California/04/2009(H1N1)) Influenza A virus (A/California/04/2009(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8T81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8T81 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]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IJM:(6M)-3-hydroxy-4-oxo-6-[(4M)-4-(1H-tetrazol-5-yl)-2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-2-carboxylic+acid'>IJM</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=8t81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8t81 OCA], [https://pdbe.org/8t81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8t81 RCSB], [https://www.ebi.ac.uk/pdbsum/8t81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8t81 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C3W5S0_I09A0 C3W5S0_I09A0] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PA(N)) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PA(N). To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PA(N) using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PA(N). Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.,Kohlbrand AJ, Stokes RW, Sankaran B, Cohen SM Biochemistry. 2024 Feb 6;63(3):264-272. doi: 10.1021/acs.biochem.3c00536. Epub , 2024 Jan 8. PMID:38190441<ref>PMID:38190441</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8t81" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Cohen SM]]
[[Category: Kohlbrand AJ]]