View source for 8dip


==The crystal structure of I38T mutant PA endonuclease (2009/H1N1/CALIFORNIA) in complex with compound SJ001023030==
<StructureSection load='8dip' size='340' side='right'caption='[[8dip]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dip]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus Influenza A virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DIP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DIP 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]] 2.5&#8491;</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=QQ4:Hexa+Vinylpyrrolidone+K15'>QQ4</scene>, <scene name='pdbligand=SE9:(2P)-5-hydroxy-N-[2-(2-methoxypyridin-4-yl)ethyl]-6-oxo-2-[3-(trifluoromethyl)phenyl]-1,6-dihydropyrimidine-4-carboxamide'>SE9</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=8dip FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dip OCA], [https://pdbe.org/8dip PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dip RCSB], [https://www.ebi.ac.uk/pdbsum/8dip PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dip ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Influenza is one of the leading causes of disease-related mortalities worldwide. Several strategies have been implemented during the past decades to hinder the replication cycle of influenza viruses, all of which have resulted in the emergence of resistant virus strains. The most recent example is baloxavir marboxil, where a single mutation in the active site of the target endonuclease domain of the RNA-dependent-RNA polymerase renders the recent FDA approved compound approximately 1000-fold less effective. Raltegravir is a first-in-class HIV inhibitor that shows modest activity to the endonuclease. Here, we have used structure-guided approaches to create rationally designed derivative molecules that efficiently engage the endonuclease active site. The design strategy was driven by our previously published structures of endonuclease-substrate complexes, which allowed us to target functionally conserved residues and reduce the likelihood of resistance mutations. We succeeded in developing low nanomolar equipotent inhibitors of both wild-type and baloxavir-resistant endonuclease. We also developed macrocyclic versions of these inhibitors that engage the active site in the same manner as their 'open' counterparts but with reduced affinity. Structural analyses provide clear avenues for how to increase the affinity of these cyclic compounds.

Chemical scaffold recycling: Structure-guided conversion of an HIV integrase inhibitor into a potent influenza virus RNA-dependent RNA polymerase inhibitor designed to minimize resistance potential.,Slavish PJ, Cuypers MG, Rimmer MA, Abdolvahabi A, Jeevan T, Kumar G, Jarusiewicz JA, Vaithiyalingam S, Jones JC, Bowling JJ, Price JE, DuBois RM, Min J, Webby RJ, Rankovic Z, White SW Eur J Med Chem. 2023 Feb 5;247:115035. doi: 10.1016/j.ejmech.2022.115035. Epub , 2022 Dec 22. PMID:36603507<ref>PMID:36603507</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dip" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Influenza A virus]]
[[Category: Large Structures]]
[[Category: Cuypers MG]]
[[Category: Rankovic Z]]
[[Category: Slavish JP]]
[[Category: White SW]]