TY - JOUR
T1 - Understanding how the herpes thymidine kinase orchestrates optimal sugar and nucleobase conformations to accommodate its substrate at the active site
T2 - A chemical approach
AU - Marquez, Victor E.
AU - Choi, Yongseok
AU - Comin, Maria Julieta
AU - Russ, Pamela
AU - George, Clifford
AU - Huleihel, Mahmoud
AU - Ben-Kasus, Tsipi
AU - Agbaría, Riad
PY - 2005/11/2
Y1 - 2005/11/2
N2 - 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.
AB - 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.
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U2 - 10.1021/ja053789s
DO - 10.1021/ja053789s
M3 - Article
C2 - 16248655
AN - SCOPUS:27544433014
VL - 127
SP - 15145
EP - 15150
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 43
ER -