Mechanism of allosteric activation of SIRT6 revealed by the action of rationally designed activators

• 作者: Shaoyong Lu Yingyi Chen Jiacheng Wei Mingzhu Zhao Duan Ni Xinheng He Jian Zhang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Short communication
• 页码范围: 1355-1361
• 页数: 7页
• 语种: 英文

摘要

The recent discovery of activator compounds binding to an allosteric site on the NAD+-dependent protein lysine deacetylase,sirtuin 6(SIRT6)has attracted interest and presents a pharmaceu-tical target for aging-related and cancer diseases.However,the mechanism underlying allosteric activa-tion of SIRT6 by the activator MDL-801 remains largely elusive because no major conformational changes are observed upon activator binding.By combining molecular dynamics simulations with biochemical and kinetic analyses of wild-type SIRT6 and its variant M136A,we show that conforma-tional rotation of 2-methyl-4-fluoro-5-bromo substituent on the right phenyl ring(R-ring)of MDL-801,which uncovers previously unseen hydrophobic interactions,contributes to increased activating dea-cetylation activity of SIRT6.This hypothesis is further supported by the two newly synthesized MDL-801 derivatives through the removal of the 5-Br atom on the R-ring(MDL-801-D1)or the restraint of the rota-tion of the R-ring(MDL-801-D2).We further propose that the 5-Br atom serves as an allosteric driver that controls the ligand allosteric efficacy.Our study highlights the effect of allosteric enzyme catalytic activity by activator binding and provides a rational approach for enhancing deacetylation activity.