View source for 7kaf


==The crystal structure of the 2009/H1N1/California PA endonuclease I38T (construct with truncated loop 51-72) in complex with baloxavir acid==
<StructureSection load='7kaf' size='340' side='right'caption='[[7kaf]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kaf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus Influenza A virus] and [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Luxembourg/43/2009(H1N1)) Influenza A virus (A/Luxembourg/43/2009(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KAF 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]] 2.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E4Z:Baloxavir+acid'>E4Z</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=QQ4:Hexa+Vinylpyrrolidone+K15'>QQ4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7kaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kaf OCA], [https://pdbe.org/7kaf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kaf RCSB], [https://www.ebi.ac.uk/pdbsum/7kaf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kaf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C6H0Y9_9INFA C6H0Y9_9INFA] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. The anti-influenza drug baloxavir is highly effective, but is associated with resistance mutations that threaten its clinical efficacy. The endonuclease resides within the N-terminal domain of the PA subunit (PAN) of the influenza RNA dependent RNA polymerase, and we report here complexes of PAN with RNA and DNA oligonucleotides to understand its specificity and the structural basis of baloxavir resistance mutations. The RNA and DNA oligonucleotides bind within the substrate binding groove of PAN in a similar fashion, explaining the ability of the enzyme to cleave both substrates. The individual nucleotides occupy adjacent conserved pockets that flank the two-metal active site. However, the 2' OH of the RNA ribose moieties engage in additional interactions that appear to optimize the binding and cleavage efficiency for the natural substrate. The major baloxavir resistance mutation at position 38 is at the core of the substrate binding site, but structural studies and modeling suggest that it maintains the necessary virus fitness via compensating interactions with RNA. These studies will facilitate the development of new influenza therapeutics that spatially match the substrate and are less likely to elicit resistance mutations.

Structural insights into the substrate specificity of the endonuclease activity of the influenza virus cap-snatching mechanism.,Kumar G, Cuypers M, Webby RR, Webb TR, White SW Nucleic Acids Res. 2021 Jan 19. pii: 6104438. doi: 10.1093/nar/gkaa1294. PMID:33469660<ref>PMID:33469660</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7kaf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Influenza A virus]]
[[Category: Large Structures]]
[[Category: Cuypers MG]]
[[Category: Kumar G]]
[[Category: Slavish J]]
[[Category: White SW]]