Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases

Anna Gardberg, Ludmilla Shuvalova, Christian Monnerjahn, Manfred Konrad, Arnon Lavie*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i) thymidine and ADP, (ii) thymidine and SO4 and the bisubstrate analogs, (iii) TP4A, and (iv) TP5A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP5A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.

Original languageEnglish (US)
Pages (from-to)1265-1277
Number of pages13
JournalStructure
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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