Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate
作者： Jiahui Wu , Dengyou Zhang , Lei Chen , Jianneng Li , Jianling Wang
DOI: 10.1021/JM301032J
关键词:
摘要: SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of activators. The activation dependent on the fluorophore labeled to substrate. To elucidate mechanism, solved crystal structure SIRT3/ac-RHKK(ac)-AMC complex. revealed that blocked H-bond formation and created cavity between substrate Rossmann fold. We built SIRT1/ac-RHKK(ac)-AMC complex model based structure. K(m) K(d) determinations demonstrated decreased peptide binding affinity. modes indicated portion interacts with through π-stacking, while other inserts into or fold, thus increasing Our study provides insights mechanism may aid design novel
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