View source for 6fsb


==Influenza B/Memphis/13/03 endonuclease with I38T mutation==
<StructureSection load='6fsb' size='340' side='right' caption='[[6fsb]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6fsb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FSB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FSB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fsb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fsb OCA], [http://pdbe.org/6fsb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fsb RCSB], [http://www.ebi.ac.uk/pdbsum/6fsb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fsb ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In clinical trials, single doses of BXM profoundly decrease viral titers as well as alleviating influenza symptoms. Here, we characterize the impact on BXA susceptibility and replicative capacity of variant viruses detected in the post-treatment monitoring of the clinical studies. We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC50 changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro. Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These mechanistic insights provide markers for future surveillance of treated populations.

Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.,Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, Kawaguchi K, Uehara T, Shishido T, Naito A, Cusack S Sci Rep. 2018 Jun 25;8(1):9633. doi: 10.1038/s41598-018-27890-4. PMID:29941893<ref>PMID:29941893</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 6fsb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Cusack, S]]
[[Category: Speranzini, V]]
[[Category: Endonuclease]]
[[Category: Influenza polymerase]]
[[Category: Viral protein]]