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 pharmaceutical target for aging-related ...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 pharmaceutical target for aging-related and cancer diseases.However,the mechanism underlying allosteric activation 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 M136 A,we show that conformational 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 deacetylation 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 rotation 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.展开更多
基金supported in part by grants from the National Natural Science Foundation of China(21778037,81901423,81903458,81925034,91753117 and 81721004,22077082)China Postdoctoral Science Foundation(2019M660090)+2 种基金the Innovation Program of Shanghai Municipal Education Commission(2019-0107-00-01-E00036,China)the Shanghai Science and Technology Innovation(19431901600,China)the Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program(2018BR12,China)。
文摘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 pharmaceutical target for aging-related and cancer diseases.However,the mechanism underlying allosteric activation 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 M136 A,we show that conformational 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 deacetylation 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 rotation 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.
