4fz3 | pdb_00004fz3
Crystal structure of SIRT3 in complex with acetyl p53 peptide coupled with 4-amino-7-methylcoumarin
Structural highlights
FunctionSIR3_HUMAN NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.[1] [2] [3] [4] Publication Abstract from PubMedSIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKK(ac)-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK(ac)-AMC complex model based on the crystal structure. K(m) and K(d) determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through pi-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators. Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate.,Wu J, Zhang D, Chen L, Li J, Wang J, Ning C, Yu N, Zhao F, Chen D, Chen X, Chen K, Jiang H, Liu H, Liu D J Med Chem. 2013 Feb 14;56(3):761-80. doi: 10.1021/jm301032j. Epub 2013 Jan 28. PMID:23316803[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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