Crystallographic structure of a small molecule SIRT1 activator-enzyme complex
| Autor: | Minghui Wang, Han Dai, George P. Vlasuk, Thomas Considine, Junfeng Wang, Richard Dana Caldwell, Christopher Oalmann, Jeremy S. Disch, Huizhen Zhao, Bruce G. Szczepankiewicz, Yong Jiang, Radha Narayan, Francis Bourbonais, Joseph Wu, Robert B. Perni, Pui Yee Ng, Bo Wu, Yoshitomo Hamuro, Benjamin Schwartz, Sharon Sweitzer, Dongming Qian, Charles A. Blum, Cheney Mao, Fan Jiang, Brian H. White, Rebecca Casaubon, April Case, Karsten Koppetsch, Erding Hu, Thomas V. Riera, Jessica E. Lee, James L. Ellis, Beth Pietrak |
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| Rok vydání: | 2015 |
| Předmět: |
Enzyme complex
Stereochemistry Genetic Vectors General Physics and Astronomy Plasma protein binding Molecular Dynamics Simulation Crystallography X-Ray Transfection Article Mass Spectrometry General Biochemistry Genetics and Molecular Biology Sirtuin 1 Catalytic Domain Hydrolase Escherichia coli Humans Amino Acid Sequence Binding site Peptide sequence chemistry.chemical_classification Binding Sites Multidisciplinary Chemistry Lysine Deuterium Exchange Measurement General Chemistry Small molecule Amino acid Biochemistry Mutagenesis Site-Directed NAD+ kinase Crystallization Protein Binding |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms8645 |
| Popis: | 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. Sirtuins are NAD+-dependent deacylases implicated in the regulation of stress responses, bioenergetics and epigenetic control. Here the authors describe the crystal structure of a sirtuin-activating compounds (STAC)-sirtuin complex and begin to elucidate the mechanism of sirtuins activation by STACs. |
| Databáze: | OpenAIRE |
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