The 2.5 脜 Crystal Structure of the SIRT1 Catalytic Domain Bound to Nicotinamide Adenine Dinucleotide (NAD+) and an Indole (EX527 Analogue) Reveals a Novel Mechanism of Histone Deacetylase I

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：963-969
• 全文大小：395K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

The sirtuin SIRT1 is a NAD⁺-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 PPAR纬, NF魏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 脜 crystal structure of the SIRT1 catalytic domain (residues 241鈥?16) bound to NAD⁺ and the 27 analogue 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.