5dbs: Difference between revisions
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==2009 H1N1 PA endonuclease mutant E119D in complex with dTMP== | ==2009 H1N1 PA endonuclease mutant E119D in complex with dTMP== | ||
<StructureSection load='5dbs' size='340' side='right' caption='[[5dbs]], [[Resolution|resolution]] 2.11Å' scene=''> | <StructureSection load='5dbs' size='340' side='right'caption='[[5dbs]], [[Resolution|resolution]] 2.11Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5dbs]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DBS OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5dbs]] 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=5DBS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DBS FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMP:THYMIDINE-5-PHOSPHATE'>TMP</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMP:THYMIDINE-5-PHOSPHATE'>TMP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5dbs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dbs OCA], [https://pdbe.org/5dbs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dbs RCSB], [https://www.ebi.ac.uk/pdbsum/5dbs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dbs ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/C3W5S0_I09A0 C3W5S0_I09A0] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains. | |||
Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor.,Song MS, Kumar G, Shadrick WR, Zhou W, Jeevan T, Li Z, Slavish PJ, Fabrizio TP, Yoon SW, Webb TR, Webby RJ, White SW Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3669-74. doi:, 10.1073/pnas.1519772113. Epub 2016 Mar 14. PMID:26976575<ref>PMID:26976575</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5dbs" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Kumar G]] | ||
[[Category: | [[Category: White SW]] | ||
Latest revision as of 11:45, 27 September 2023
2009 H1N1 PA endonuclease mutant E119D in complex with dTMP2009 H1N1 PA endonuclease mutant E119D in complex with dTMP
Structural highlights
FunctionPublication Abstract from PubMedThe influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains. Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor.,Song MS, Kumar G, Shadrick WR, Zhou W, Jeevan T, Li Z, Slavish PJ, Fabrizio TP, Yoon SW, Webb TR, Webby RJ, White SW Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3669-74. doi:, 10.1073/pnas.1519772113. Epub 2016 Mar 14. PMID:26976575[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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