Crystallographic structure of a small molecule SIRT1 activator-enzyme complex

Han Dai (), April W. Case, Thomas V. Riera, Thomas Considine, Jessica E. Lee, Yoshitomo Hamuro, Huizhen Zhao, Yong Jiang, Sharon M. Sweitzer, Beth Pietrak, Benjamin Schwartz, Charles A. Blum, Jeremy S. Disch, Richard Caldwell, Bruce Szczepankiewicz, Christopher Oalmann, Pui Yee Ng, Brian H. White, Rebecca Casaubon, Radha Narayan, Karsten Koppetsch, Francis Bourbonais, Bo Wu, Junfeng Wang, Dongming Qian, Fan Jiang, Cheney Mao, Minghui Wang, Erding Hu, Joe C. Wu, Robert B. Perni, George P. Vlasuk and James L. Ellis
Additional contact information
Han Dai: Sirtris, a GlaxoSmithKline Company
April W. Case: Sirtris, a GlaxoSmithKline Company
Thomas V. Riera: Sirtris, a GlaxoSmithKline Company
Thomas Considine: Sirtris, a GlaxoSmithKline Company
Jessica E. Lee: ExSAR Corporation
Yoshitomo Hamuro: ExSAR Corporation
Huizhen Zhao: GlaxoSmithKline
Yong Jiang: GlaxoSmithKline
Sharon M. Sweitzer: GlaxoSmithKline
Beth Pietrak: GlaxoSmithKline
Benjamin Schwartz: GlaxoSmithKline
Charles A. Blum: Sirtris, a GlaxoSmithKline Company
Jeremy S. Disch: Sirtris, a GlaxoSmithKline Company
Richard Caldwell: Sirtris, a GlaxoSmithKline Company
Bruce Szczepankiewicz: Sirtris, a GlaxoSmithKline Company
Christopher Oalmann: Sirtris, a GlaxoSmithKline Company
Pui Yee Ng: Sirtris, a GlaxoSmithKline Company
Brian H. White: Sirtris, a GlaxoSmithKline Company
Rebecca Casaubon: Sirtris, a GlaxoSmithKline Company
Radha Narayan: Sirtris, a GlaxoSmithKline Company
Karsten Koppetsch: Sirtris, a GlaxoSmithKline Company
Francis Bourbonais: Sirtris, a GlaxoSmithKline Company
Bo Wu: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences
Junfeng Wang: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences
Dongming Qian: Viva Biotech
Fan Jiang: Viva Biotech
Cheney Mao: Viva Biotech
Minghui Wang: GlaxoSmithKline
Erding Hu: GlaxoSmithKline
Joe C. Wu: Sirtris, a GlaxoSmithKline Company
Robert B. Perni: Sirtris, a GlaxoSmithKline Company
George P. Vlasuk: Sirtris, a GlaxoSmithKline Company
James L. Ellis: Sirtris, a GlaxoSmithKline Company

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8645

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