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Crystallographic structure of a small molecule SIRT1 activator-enzyme complex

Author

Listed:
  • Han Dai

    (Sirtris, a GlaxoSmithKline Company
    GlaxoSmithKline)

  • 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
    GlaxoSmithKline)

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.

Suggested Citation

  • 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 &, 2015. "Crystallographic structure of a small molecule SIRT1 activator-enzyme complex," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8645
    DOI: 10.1038/ncomms8645
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