Document Detail

The 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analog) reveals a novel mechanism of histone deacetylase inhibition.
MedLine Citation:
PMID:  23311358     Owner:  NLM     Status:  Publisher    
The sirtuin SIRT1 is a NAD-dependent 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 PPAR, NFB, and the tumor suppressor protein p53. EX527 (27) is a nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate the mechanism of SIRT inhibition by 27, we determined the 2.5 Å crystal structure of the SIRT1 catalytic domain (residues 241-516) bound to NAD and the 27 analog compound 35. 35 binds deep in the catalytic cleft displacing the NAD nicotinamide and forcing the cofactor into an extended conformation. The extended NAD conformation sterically prevents substrate binding. The SIRT1/NAD/35 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.
Xun Zhao; Dagart Allison; Bradley Condon; Feiyu Zhang; Tarun Gheyi; Aiping Zhang; Sheela Ashok; Marijane Russell; Iain Macewan; Yuewei Qian; James A Jamison; John Gately Luz
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-11
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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