Full text

Turn on search term navigation

Copyright Nature Publishing Group Jul 2015

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.

Details

Title
Crystallographic structure of a small molecule SIRT1 activator-enzyme complex
Author
Dai, Han; Case, April W; Riera, Thomas V; Considine, Thomas; Lee, Jessica E; Hamuro, Yoshitomo; Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M; Pietrak, Beth; Schwartz, Benjamin; Blum, Charles A; Disch, Jeremy S; Caldwell, Richard; Szczepankiewicz, Bruce; Oalmann, Christopher; Yee Ng, Pui; White, Brian H; Casaubon, Rebecca; Narayan, Radha; Koppetsch, Karsten; Bourbonais, Francis; Wu, Bo; Wang, Junfeng; Qian, Dongming; Jiang, Fan; Mao, Cheney; Wang, Minghui; Hu, Erding; Wu, Joe C; Perni, Robert B; Vlasuk, George P; Ellis, James L
Pages
7645
Publication year
2015
Publication date
Jul 2015
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1692776739
Copyright
Copyright Nature Publishing Group Jul 2015