Understanding how the herpes thymidine kinase orchestrates optimal sugar and nucleobase conformations to accommodate its substrate at the active site: A chemical approach

Victor E. Marquez, Yongseok Choi, Maria Julieta Comin, Pamela Russ, Clifford George, Mahmoud Huleihel, Tsipi Ben-Kasus, Riad Agbaría

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36 Citations (Scopus)

Abstract

The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, a successful therapeutic outcome depends not only on the activity of this enzyme but also on the ability of the compound(s) to interact effectively with cellular kinases and with the target viral or cellular DNA polymerases. Herein, we describe the synthesis and study of two nucleoside analogues built on a conformationally locked bicyclo[3.1.0]hexane template designed to investigate the conformational preferences of HSV-tk for the 2′-deoxyribose ring. Intimately associated with the conformation of the 2′-deoxyribose ring is the value of the C-N torsion angle χ, which positions the nucleobase into two different domains (syn or anti), The often-conflicting sugar and nucleobase conformational parameters were studied using North and South methanocarbadeoxythymidine analogues (6 and 7), which forced HSV-tk to make a clear choice in the conformation of the substrate. The results provide new insights into the mechanism of action of this enzyme, which cannot be gleaned from a static X-ray crystal structure.

Original languageEnglish
Pages (from-to)15145-15150
Number of pages6
JournalJournal of the American Chemical Society
Volume127
Issue number43
DOIs
Publication statusPublished - 2005 Nov 2
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)

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