4ZZI

SIRT1/Activator/Inhibitor Complex

4ZZI の概要

• エントリーDOI: 10.2210/pdb4zzi/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-1, (3S)-1,3-dimethyl-N-[3-(1,3-oxazol-5-yl)phenyl]-6-[3-(trifluoromethyl)phenyl]-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide, 4-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide, ... (5 entities in total)
• 機能のキーワード: sirtuin, activator, deacylase, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus, PML body. SirtT1 75 kDa fragment: Cytoplasm: Q96EB6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41067.64

構造登録者

Dai, H. (登録日: 2015-05-22, 公開日: 2015-07-15, 最終更新日: 2023-09-27)

主引用文献

Dai, H.,Case, A.W.,Riera, T.V.,Considine, T.,Lee, J.E.,Hamuro, Y.,Zhao, H.,Jiang, Y.,Sweitzer, S.M.,Pietrak, B.,Schwartz, B.,Blum, C.A.,Disch, J.S.,Caldwell, R.,Szczepankiewicz, B.,Oalmann, C.,Yee Ng, P.,White, B.H.,Casaubon, R.,Narayan, R.,Koppetsch, K.,Bourbonais, F.,Wu, B.,Wang, J.,Qian, D.,Jiang, F.,Mao, C.,Wang, M.,Hu, E.,Wu, J.C.,Perni, R.B.,Vlasuk, G.P.,Ellis, J.L.
Crystallographic structure of a small molecule SIRT1 activator-enzyme complex.
Nat Commun, 6:7645-7645, 2015

PubMed Abstract: SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.

PubMed: 26134520
DOI: 10.1038/ncomms8645

実験手法

X-RAY DIFFRACTION (2.7346 Å)