The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): Implications for the development of dCK-activated acyclic guanine analogues.

摘要: The low toxicity of acyclovir (ACV) is mainly due to the fact that human nucleoside kinases have undetectable phosphorylation rates with this acyclic guanine analogue. In contrast, herpes virus thymidine kinase (HSV1-TK) readily activates ACV. We wanted understand why deoxycytidine (dCK), which related HSV1-TK and phosphorylates deoxyguanosine, does not accept analogues as substrates. Therefore, we crystallized dCK in complex ACV at phosphoryl acceptor site UDP donor site. structure reveals while bind active site, it so adopting a nonproductive conformation. Despite binding ACV, enzyme remains open, inactive state. comparison HSV1-TK, dCK, base adopts different orientation by about 60° rotation. Our analysis suggests would phosphorylate if they can induce similar