title: Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation.
abstract: Resveratrol is a natural compound found in red wine that has been suggested to exert its potential health benefit through the activation of SIRT1, a crucial member of the mammalian NAD+-dependent deacetylases. SIRT1 has emerged as an attractive therapeutic target for many aging related diseases, however, how its activity can only be activated toward some specific substrates by resveratrol has been poorly understood. Herein, by employing extensive molecular dynamics simulations as well as fragment-centric topographical mapping of binding interfaces, we have clarified current controversies in the literature and elucidated that resveratrol plays an important activation role by stabilizing SIRT1/peptide interactions in a substrate-specific manner. This new mechanism highlights the importance of the N-terminal domain in substrate recognition, explains the activity restoration role of resveratrol toward some "loose-binding" substrates of SIRT1, and has significant implications for the rational design of new substrate-specific SIRT1 modulators.
authors.affiliation: Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China.|Department of Chemistry, New York University, New York, New York, 10003, United States.
authors.forename: Xuben
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Chemistry, New York University, New York, New York, 10003, United States.
authors.forename: David
authors.initials: D
authors.lastname: Rooklin
authors.affiliation: Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.affiliation: Department of Chemistry, New York University, New York, New York, 10003, United States.|NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, 200062, China.
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D055550:Protein Stability / Q000187:drug effects; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000737:chemistry* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
chemical_list: D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol