{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:54:56Z","timestamp":1789577696480,"version":"build-2803163510"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2015,12,2]],"date-time":"2015-12-02T00:00:00Z","timestamp":1449014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0143947","type":"journal-article","created":{"date-parts":[[2015,12,2]],"date-time":"2015-12-02T19:10:44Z","timestamp":1449083444000},"page":"e0143947","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["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"],"prefix":"10.1371","volume":"10","author":[{"given":"Kelly","family":"Hew","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue-Li","family":"Dahlroth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saranya","family":"Veerappan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy Xin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Cornvik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4r","family":"Nordlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,12,2]]},"reference":[{"issue":"9","key":"ref1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1056\/NEJM200003023420906","article-title":"Neurologic complications of the reactivation of varicella\u2013zoster virus","volume":"342","author":"DH Gilden","year":"2000","journal-title":"New England Journal of Medicine"},{"key":"ref2","article-title":"Varicella-zoster virus DNA in human sensory ganglia","author":"DH Gilden","year":"1983","journal-title":"Varicella-zoster virus DNA in human sensory ganglia"},{"issue":"24","key":"ref3","doi-asserted-by":"crossref","first-page":"10980","DOI":"10.1073\/pnas.92.24.10980","article-title":"Reactivated and latent varicella-zoster virus in human dorsal root ganglia","volume":"92","author":"O Lungu","year":"1995","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"8","key":"ref4","first-page":"2437","article-title":"Management of herpes zoster (shingles) and postherpetic neuralgia","volume":"61","author":"SJ Stankus","year":"2000","journal-title":"American family physician"},{"issue":"9","key":"ref5","doi-asserted-by":"crossref","first-page":"a013011","DOI":"10.1101\/cshperspect.a013011","article-title":"Herpes simplex viruses: mechanisms of DNA replication","volume":"4","author":"SK Weller","year":"2012","journal-title":"Cold Spring Harbor perspectives in biology"},{"key":"ref6","article-title":"Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis","author":"ESJ Mocarski","year":"2007"},{"issue":"2","key":"ref7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jcv.2004.02.009","article-title":"Antiviral drugs in current clinical use","volume":"30","author":"E De Clercq","year":"2004","journal-title":"Journal of Clinical Virology"},{"issue":"9","key":"ref8","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nrmicro975","article-title":"Antivirals and antiviral strategies","volume":"2","author":"E De Clercq","year":"2004","journal-title":"Nat Rev Micro"},{"issue":"24","key":"ref9","doi-asserted-by":"crossref","first-page":"8721","DOI":"10.1016\/S0021-9258(17)34236-9","article-title":"Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl) guanine","volume":"253","author":"J Fyfe","year":"1978","journal-title":"Journal of Biological Chemistry"},{"issue":"3","key":"ref10","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1128\/AAC.20.3.420","article-title":"Differential activity of potential antiviral nucleoside analogs on herpes simplex virus-induced and human cellular thymidine kinases","volume":"20","author":"Y Cheng","year":"1981","journal-title":"Antimicrobial agents and chemotherapy"},{"issue":"32","key":"ref11","doi-asserted-by":"crossref","first-page":"33035","DOI":"10.1074\/jbc.R400007200","article-title":"Mammalian Pyrimidine Biosynthesis: Fresh Insights into an Ancient Pathway","volume":"279","author":"DR Evans","year":"2004","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"ref12","doi-asserted-by":"crossref","first-page":"220","DOI":"10.3816\/CCC.2002.n.003","article-title":"Thymidylate synthase: a critical target for cancer chemotherapy","volume":"1","author":"MG Rose","year":"2002","journal-title":"Clinical colorectal cancer"},{"key":"ref13","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2015.00363","article-title":"Perturbed states of the bacterial chromosome: a thymineless death case study","volume":"6","author":"L Ostrer","year":"2015","journal-title":"Frontiers in microbiology"},{"issue":"7","key":"ref14","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/0959-8049(95)00166-G","article-title":"ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer","volume":"31","author":"A Jackman","year":"1995","journal-title":"European journal of cancer"},{"issue":"12","key":"ref15","doi-asserted-by":"crossref","first-page":"4276s","DOI":"10.1158\/1078-0432.CCR-040010","article-title":"Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent","volume":"10","author":"AA Adjei","year":"2004","journal-title":"Clinical Cancer Research"},{"issue":"3","key":"ref16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1200\/JCO.1985.3.3.373","article-title":"Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil\u2014an Eastern Cooperative Oncology Group study","volume":"3","author":"D Klaassen","year":"1985","journal-title":"Journal of Clinical Oncology"},{"issue":"4787","key":"ref17","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.3099389","article-title":"Atomic structure of thymidylate synthase: target for rational drug design","volume":"235","author":"LW Hardy","year":"1987","journal-title":"Science"},{"issue":"30","key":"ref18","doi-asserted-by":"crossref","first-page":"6977","DOI":"10.1021\/bi00482a005","article-title":"Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase","volume":"29","author":"JS Finer-Moore","year":"1990","journal-title":"Biochemistry"},{"issue":"4","key":"ref19","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/0022-2836(90)90346-N","article-title":"Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2\u2032-deoxyuridylate and 10-propargyl-5, 8-dideazafolate","volume":"214","author":"D Matthews","year":"1990","journal-title":"J Mol Biol"},{"issue":"4","key":"ref20","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1006\/jmbi.1993.1463","article-title":"Refined Structures of Substrate-bound and Phosphate-bound Thymidylate Synthase from Lactobacillus casei","volume":"232","author":"J Finer-Moore","year":"1993","journal-title":"J Mol Biol"},{"issue":"50","key":"ref21","doi-asserted-by":"crossref","first-page":"16279","DOI":"10.1021\/bi00050a007","article-title":"Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site","volume":"34","author":"CA Schiffer","year":"1995","journal-title":"Biochemistry"},{"issue":"7","key":"ref22","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1021\/bi002413i","article-title":"Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug","volume":"40","author":"J Phan","year":"2001","journal-title":"Biochemistry"},{"issue":"17","key":"ref23","doi-asserted-by":"crossref","first-page":"14170","DOI":"10.1074\/jbc.M009493200","article-title":"Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors","volume":"276","author":"J Phan","year":"2001","journal-title":"Journal of Biological Chemistry"},{"issue":"6","key":"ref24","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S0969-2126(03)00097-2","article-title":"Functional analysis of substrate and cofactor complex structures of a thymidylate synthase-complementing protein","volume":"11","author":"II Mathews","year":"2003","journal-title":"Structure"},{"issue":"10","key":"ref25","doi-asserted-by":"crossref","first-page":"120120","DOI":"10.1098\/rsob.120120","article-title":"Mechanistic and structural basis for inhibition of thymidylate synthase ThyX","volume":"2","author":"T Basta","year":"2012","journal-title":"Open biology"},{"issue":"42","key":"ref26","doi-asserted-by":"crossref","first-page":"16823","DOI":"10.1073\/pnas.1204556109","article-title":"Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target","volume":"109","author":"Y Yuthavong","year":"2012","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"ref27","doi-asserted-by":"crossref","first-page":"e53851","DOI":"10.1371\/journal.pone.0053851","article-title":"Combining functional and structural genomics to sample the essential Burkholderia structome","volume":"8","author":"L Baugh","year":"2013","journal-title":"PloS one"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bioorg.2013.11.003","article-title":"Crystal structure of phosphoramide-phosphorylated thymidylate synthase reveals pSer127, reflecting probably pHis to pSer phosphotransfer","volume":"52","author":"P Wilk","year":"2014","journal-title":"Bioorganic chemistry"},{"key":"ref29","doi-asserted-by":"crossref","DOI":"10.1155\/2014\/945803","article-title":"Crystal Structure of Mouse Thymidylate Synthase in Tertiary Complex with dUMP and Raltitrexed Reveals N-Terminus Architecture and Two Different Active Site Conformations","volume":"2014","author":"A Dowiercia\u0142","year":"2014","journal-title":"BioMed research international"},{"issue":"6","key":"ref30","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1042\/BSR20140137","article-title":"Analysis of mRNA recognition by human thymidylate synthase","volume":"34","author":"ND Brunn","year":"2014","journal-title":"Bioscience reports"},{"issue":"2","key":"ref31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0925-4439(02)00083-2","article-title":"Structure-based studies on species-specific inhibition of thymidylate synthase","volume":"1587","author":"MP Costi","year":"2002","journal-title":"Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease"},{"issue":"20","key":"ref32","doi-asserted-by":"crossref","first-page":"10530","DOI":"10.1128\/JVI.76.20.10530-10532.2002","article-title":"Human herpesvirus 8 gene encodes a functional thymidylate synthase","volume":"76","author":"G G\u00e1sp\u00e1r","year":"2002","journal-title":"Journal of virology"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1099\/0022-1317-68-5-1449","article-title":"Varicella-zoster virus specifies a thymidylate synthetase","volume":"68","author":"R Thompson","year":"1987","journal-title":"J Gen Virol"},{"issue":"15","key":"ref34","doi-asserted-by":"crossref","first-page":"7376","DOI":"10.1073\/pnas.90.15.7376","article-title":"Generation of varicella-zoster virus (VZV) and viral mutants from cosmid DNAs: VZV thymidylate synthetase is not essential for replication in vitro","volume":"90","author":"JI Cohen","year":"1993","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"5","key":"ref35","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1110\/ps.47601","article-title":"Crystal structure of a deletion mutant of human thymidylate synthase \u0394 (7\u201329) and its ternary complex with Tomudex and dUMP","volume":"10","author":"R Almog","year":"2001","journal-title":"Protein Science"},{"issue":"4","key":"ref36","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1006\/jmbi.2001.5074","article-title":"Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and&lt; i&gt; Escherichia coli thymidylate synthases","volume":"313","author":"PH Sayre","year":"2001","journal-title":"J Mol Biol"},{"issue":"1","key":"ref37","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1107\/S0909049506043251","article-title":"X-ray radiation-induced damage in DNA monitored by online Raman","volume":"14","author":"JE McGeehan","year":"2007","journal-title":"Journal of synchrotron radiation"},{"issue":"4","key":"ref38","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1107\/S0907444909051609","article-title":"The magic triangle goes MAD: experimental phasing with a bromine derivative","volume":"66","author":"T Beck","year":"2010","journal-title":"Acta Crystallographica Section D: Biological Crystallography"},{"issue":"7","key":"ref39","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/annonc\/mdh264","article-title":"5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers","volume":"15","author":"P Noordhuis","year":"2004","journal-title":"Annals of oncology"},{"issue":"suppl 1","key":"ref40","doi-asserted-by":"crossref","first-page":"D901","DOI":"10.1093\/nar\/gkm958","article-title":"DrugBank: a knowledgebase for drugs, drug actions and drug targets","volume":"36","author":"DS Wishart","year":"2008","journal-title":"Nucleic Acids Res"},{"issue":"28","key":"ref41","doi-asserted-by":"crossref","first-page":"7116","DOI":"10.1021\/bi00079a007","article-title":"Structures of thymidylate synthase with a C-terminal deletion: role of the C-terminus in alignment of 2&apos;-deoxyuridine 5&apos;-monophosphate and 5, 10-methylenetetrahydrofolate","volume":"32","author":"KM Perry","year":"1993","journal-title":"Biochemistry"},{"issue":"11","key":"ref42","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/nrd1877","article-title":"Acyclic nucleoside phosphonates: a key class of antiviral drugs","volume":"4","author":"E De Clercq","year":"2005","journal-title":"Nature Reviews Drug Discovery"},{"issue":"1","key":"ref43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1592\/phco.21.1.11.34439","article-title":"Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians","volume":"21","author":"DS Stein","year":"2001","journal-title":"Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy"},{"issue":"6","key":"ref44","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1073\/pnas.76.6.2947","article-title":"(E)-5-(2-Bromovinyl)-2&apos;-deoxyuridine: a potent and selective anti-herpes agent","volume":"76","author":"E De Clercq","year":"1979","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"3","key":"ref45","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0026-895X(25)13017-4","article-title":"Thymidylate synthase is the principal target enzyme for the cytostatic activity of (E)-5-(2-bromovinyl)-2&apos;-deoxyuridine against murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 or type 2 thymidine kinase gene","volume":"32","author":"J Balzarini","year":"1987","journal-title":"Molecular pharmacology"},{"issue":"1","key":"ref46","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/S0026-895X(25)13899-6","article-title":"Differential affinities of 5-(2-halogenovinyl)-2&apos;-deoxyuridines for deoxythymidine kinases of various origins","volume":"20","author":"Y-C Cheng","year":"1981","journal-title":"Molecular pharmacology"},{"issue":"3","key":"ref47","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1177\/095632029400500309","article-title":"Inhibition of thymidylate synthetase activity induced in varicella-zoster virus infected cells by (E)-5-(2-bromovinyl)-2&apos;-deoxyuridine","volume":"5","author":"Y Yokota","year":"1994","journal-title":"Antiviral chemistry & chemotherapy"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1107\/S0909049502015170","article-title":"Blu-Ice and the Distributed Control System: software for data acquisition and instrument control at macromolecular crystallography beamlines","volume":"9","author":"TM McPhillips","year":"2002","journal-title":"Journal of Synchrotron Radiation"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray diffraction data collected in oscillation mode","volume":"276","author":"Z Otwinowski","year":"1997","journal-title":"Methods in Enzymology"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and Development of Coot","volume":"66","author":"P Emsley","year":"2010","journal-title":"Acta Crystallographica Section D: Biological Crystallography"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"PD Adams","year":"2010","journal-title":"Acta Crystallographica Section D: Biological Crystallography"},{"issue":"4","key":"ref52","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards automated crystallographic structure refinement with phenix. refine","volume":"68","author":"PV Afonine","year":"2012","journal-title":"Acta Crystallographica Section D: Biological Crystallography"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser Crystallographic Software","volume":"40","author":"AJ McCoy","year":"2007","journal-title":"Journal of Applied Crystallography"},{"issue":"Pt 4","key":"ref54","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview of the CCP4 suite and current developments","volume":"67","author":"MD Winn","year":"2011","journal-title":"Acta crystallographica Section D, Biological crystallography"},{"issue":"1","key":"ref55","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1107\/S0907444909042073","article-title":"MolProbity: all-atom structure validation for macromolecular crystallography","volume":"66","author":"VB Chen","year":"2009","journal-title":"Acta Crystallographica Section D: Biological Crystallography"},{"key":"ref56","unstructured":"DeLano W. The PyMOL Molecular Graphics System, Version 1.7.2.0. 2014."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0143947","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T16:58:49Z","timestamp":1748710729000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0143947"}},"subtitle":[],"editor":[{"given":"Anna","family":"Roujeinikova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,12,2]]},"references-count":56,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0143947","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,2]]}}}