4FZ3

Crystal structure of SIRT3 in complex with acetyl p53 peptide coupled with 4-amino-7-methylcoumarin

4FZ3 の概要

• エントリーDOI: 10.2210/pdb4fz3/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, peptide from Cellular tumor antigen p53, ZINC ION, ... (4 entities in total)
• 機能のキーワード: zinc-binding motif, rossmann fold, nad-dependent deacetylase, mitochondrial, hydrolase-hydrolase substrate complex, hydrolase/hydrolase substrate
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Mitochondrion matrix: Q9NTG7; Cytoplasm. Isoform 1: Nucleus. Isoform 2: Nucleus. Isoform 3: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 8: Nucleus. Isoform 9: Cytoplasm: P04637
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32258.50

構造登録者

Liu, D.,Wu, J.,Zhang, D.,Chen, K.,Jiang, H.,Liu, H. (登録日: 2012-07-06, 公開日: 2013-03-20, 最終更新日: 2024-11-13)

主引用文献

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.
Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate
J.Med.Chem., 56:761-780, 2013

PubMed Abstract: SIRT1 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 π-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.

PubMed: 23316803
DOI: 10.1021/jm301032j

実験手法

X-RAY DIFFRACTION (2.1 Å)