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Published February 6, 2014 | Accepted Version
Journal Article Open

Structural and Functional Analysis of Human SIRT1


SIRT1 is a NAD^+-dependent deacetylase that plays important roles in many cellular processes. SIRT1 activity is uniquely controlled by a C-terminal regulatory segment (CTR). Here we present crystal structures of the catalytic domain of human SIRT1 in complex with the CTR in an open apo form and a closed conformation in complex with a cofactor and a pseudo-substrate peptide. The catalytic domain adopts the canonical sirtuin fold. The CTR forms a β hairpin structure that complements the β sheet of the NAD^+-binding domain, covering an essentially invariant hydrophobic surface. The apo form adopts a distinct open conformation, in which the smaller subdomain of SIRT1 undergoes a rotation with respect to the larger NAD^+-binding subdomain. A biochemical analysis identifies key residues in the active site, an inhibitory role for the CTR, and distinct structural features of the CTR that mediate binding and inhibition of the SIRT1 catalytic domain.

Additional Information

© 2013 Elsevier B.V. Available online 10 October 2013. Received 30 July 2013; Received in revised form 27 September 2013; Accepted 4 October 2013. Available online xxxx. In Press, Corrected Proof — Note to users. We thank Erik W. Debler, Daniel H. Lin, Alina Patke, Pete Stavropoulos, Tobias Stuwe, and Yunji Wu for critical reading of the manuscript; Leslie N. Collins for technical support; David King for mass spectrometry analysis; Anders Näär for providing material; and Jens Kaiser and the scientific staff of SSRL beamline 12-2, as well as Corie Ralston and the scientific staff of Advanced (Light (APLS) Source beamline 8.2.2, for their support with X-ray diffraction measurements. We acknowledge the Gordon and Betty Moore Foundation for their support of the Molecular Observatory at the California Institute of Technology. The operations at the SSRL and ALS are supported by the Department of Energy and by the National Institutes of Health. A.M.D. is supported by a National Institutes of Health Research Service Award (5T32 GM07616). A.H. was supported by the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research.

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Accepted Version - nihms607375.pdf


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