Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha

Abstract

BackgroundResveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed.ResultsHere, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα.ConclusionsOur Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.

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“…The dynamic behavior observed in this region has also been reported in many agonist/antagonist simulation studies. 66,67 Simulations of the apo systems show slightly different RMSF values in the same region as compared to those of the antagonist forms. Moreover, the free agonist systems have similar dynamic regions as those of the apo and antagonist systems, with decreased uctuations in a loop preceding H9 (residues 460-466), and this agrees well with a previous simulation study involving hERa.…”

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“…Recently, resveratrol has been widely marketed with much hype that it can be used to cure anything from Alzheimer's disease to cancer, despite the scarcity of evidence supporting such claims. Preclinical studies reflect a potential chemopreventive role for resveratrol, as it promotes apoptosis, regulates cell cycling, and inhibits cyclooxygenase and prostaglandin synthesis while acting as an antioxidant, thereby preventing DNA damage that can lead to tumor formation 179 , 180 …”

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“…This is a pity, given the pleiotropic effects this dietary compound is reported to have in important pathophysiological respects (for recent reviews see, e.g., [25][26][27][28][29][30]). Possibly its most widely discussed activities are as an activator of the deacetylase SIRT1 and a repressor of inflammation, to which one might add its estrogen-like features (e.g., [31][32][33][34][35][36][37][38]). Pronounced metabolism may be an important reason why resveratrol's effects are often unclear in human clinical studies [39][40][41][42][43][44]-a weakness shared with other polyphenols.…”