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The | ==Complex structure of thymidylate synthase from varicella zoster virus with a dUMP== | ||
<StructureSection load='4xsd' size='340' side='right'caption='[[4xsd]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4xsd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_herpesvirus_3_strain_Oka_vaccine Human herpesvirus 3 strain Oka vaccine]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XSD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XSD 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]] 2.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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=4xsd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xsd OCA], [https://pdbe.org/4xsd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xsd RCSB], [https://www.ebi.ac.uk/pdbsum/4xsd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xsd ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TYSY_VZVO TYSY_VZVO] Catalyzes the reductive methylation of deoxyuridylate to thymidylate. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP de novo. To study substrate binding, the complex structure of TSVZV with dUMP was determined to a resolution of 2.9 A. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TSHS) in an open conformation. The interactions between TSVZV with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TSVZV binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TSVZV and in vitro phosphorylated brivudine (BVDUP), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDUP to TSVZV was further confirmed by the complex structure of TSVZV and BVDUP solved at a resolution of 2.9 A. BVDUP binds similarly as dUMP in the TSHS but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDUP is likely to inhibit TSVZV by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TSVZV and BVDUP are consistent with that TSVZV is indeed a target of brivudine in vivo. The work also provided the structural basis for rational design of more specific TSVZV inhibitors. | |||
Structure of the Varicella Zoster Virus Thymidylate Synthase Establishes Functional and Structural Similarities as the Human Enzyme and Potentiates Itself as a Target of Brivudine.,Hew K, Dahlroth SL, Veerappan S, Pan LX, Cornvik T, Nordlund P PLoS One. 2015 Dec 2;10(12):e0143947. doi: 10.1371/journal.pone.0143947., eCollection 2015. PMID:26630264<ref>PMID:26630264</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Hew | <div class="pdbe-citations 4xsd" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human herpesvirus 3 strain Oka vaccine]] | |||
[[Category: Large Structures]] | |||
[[Category: Hew K]] | |||