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==HSV1 polymerase ternary complex with dsDNA and PNU-183792==
<StructureSection load='7luf' size='340' side='right'caption='[[7luf]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7luf]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_alphaherpesvirus_1 Human alphaherpesvirus 1] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LUF 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]] 3.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YE4:N-(4-chlorobenzyl)-1-methyl-6-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide'>YE4</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=7luf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7luf OCA], [https://pdbe.org/7luf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7luf RCSB], [https://www.ebi.ac.uk/pdbsum/7luf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7luf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DPOL_HHV11 DPOL_HHV11] Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding protein. Additionally, the polymerase contains an intrinsic ribonuclease H (RNase H) activity that specifically degrades RNA/DNA heteroduplexes or duplex DNA substrates in the 5' to 3' direction. Therefore, it can catalyze the excision of the RNA primers that initiate the synthesis of Okazaki fragments at a replication fork during viral DNA replication.<ref>PMID:2553735</ref> 
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== Publication Abstract from PubMed ==
All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 A resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.

Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase.,Hayes RP, Heo MR, Mason M, Reid J, Burlein C, Armacost KA, Tellers DM, Raheem I, Shaw AW, Murray E, McKenna PM, Abeywickrema P, Sharma S, Soisson SM, Klein D Nat Commun. 2021 May 24;12(1):3040. doi: 10.1038/s41467-021-23312-8. PMID:34031403<ref>PMID:34031403</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7luf" style="background-color:#fffaf0;"></div>

==See Also==
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human alphaherpesvirus 1]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Hayes RP]]
[[Category: Klein D]]