The 2.5 Å Crystal
Structure of the SIRT1 Catalytic
Domain Bound to Nicotinamide Adenine Dinucleotide (NAD<sup>+</sup>) and an Indole (EX527 Analogue) Reveals a Novel Mechanism of Histone
Deacetylase Inhibition
- Publication date
- Publisher
Abstract
The sirtuin SIRT1 is a NAD<sup>+</sup>-dependent histone
deacetylase,
a Sir2 family member, and one of seven human sirtuins. Sirtuins are
conserved from archaea to mammals and regulate transcription, genome
stability, longevity, and metabolism. SIRT1 regulates transcription
via deacetylation of transcription factors such as PPARγ, NFκB,
and the tumor suppressor protein p53. EX527 (<b>27</b>) is a
nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate
the mechanism of SIRT inhibition by <b>27</b>, we determined
the 2.5 Å crystal structure of the SIRT1 catalytic domain (residues
241–516) bound to NAD<sup>+</sup> and the <b>27</b> analogue
compound <b>35</b>. <b>35</b> binds deep in the catalytic
cleft, displacing the NAD<sup>+</sup> nicotinamide and forcing the
cofactor into an extended conformation. The extended NAD<sup>+</sup> conformation sterically prevents substrate binding. The SIRT1/NAD<sup>+</sup>/<b>35</b> crystal structure defines a novel mechanism
of histone deacetylase inhibition and provides a basis for understanding,
and rationally improving, inhibition of this therapeutically important
target by drug-like molecules