Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Nwachukwu, Jerome C.; Srinivasan, Sathish; Bruno, Nelson E.; Parent, A.A.; Hughes, Travis S.; Pollock, Julie A.; Gjyshi, Olsi; Cavett, V.; Nowak, J.; Garcia-Ordoñez, Rubén D.; Houtman, René; Griffin, Patrick R.; Kojetin, D.J.; Katzenellenbogen, John A.; Conkright, Michael D.; Nettles, K.W.

doi:10.7554/elife.02057

Cited by 121 publications

(111 citation statements)

References 98 publications

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“…signalingcompetent) and "non-productive" binding modes in the orthosteric site of M 1 AChRs (50). Moreover, for ligand-activated nuclear receptors, ligand binding ensembles have been crystallized (51)(52)(53)(54)(55) and might hence appear as a general principle in protein-ligand interactions. In the case of GPCRs, biophysical techniques, single molecule studies, and the dynophore approach may be helpful to address whether purely orthosteric agonists can form a ligand binding ensemble consisting of active and inactive agonist⅐receptor complexes.…”

Section: Discussionmentioning

confidence: 99%

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Böck

Bermudez

Krebs

et al. 2016

Journal of Biological Chemistry

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G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood.Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M 2 receptors to demonstrate the existence and function of such inactive agonist⅐receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist⅐receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist⅐receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.Specific and coordinated cell-to-cell communication regulates the flow of information between cells, and proper information processing ensures physiological functions of biological systems. G protein-coupled receptors (GPCRs), 8 constituting the largest class of membrane proteins in mammals, are essential mediators of chemically and light-encoded information (1-4). GPCRs sense a great variety of extracellular stimuli, e.g. neurotransmitters and hormones, and subsequently translate this information into an intracellular response via G proteins, ␤-arrestins, and possibly GPCR-interacting proteins (2-5). Because of their abundance and relevance in regulating the majority of (patho-)physiological processes in humans, GPCRs have for a long time represented the most important drug targets being addressed by at least a third of all currently marketed drugs (6, 7).Agonist binding leads to receptor activation, which is followed by intracellular G protein recruitment and subsequent cell signaling. Breakthroughs in GPCR crystallography have led to inactive and active crystal structures of the same receptor protein. Among these are rhodopsin (8 -10) and more recently the ␤ 2 -adrenergic (11-14), M 2 muscarinic (15, 16), and -opioid receptors (17, 18). These structures most likely represent energetically favored, relatively stable inactive and active receptor⅐ligand complexes. Despite the diversity of crystallized receptors, a common...

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Section: Discussionmentioning

confidence: 99%

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Böck

Bermudez

Krebs

et al. 2016

Journal of Biological Chemistry

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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.…”

Section: Introductionmentioning

confidence: 99%

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

et al. 2015

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Abstract:Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3-[OCH2CH2]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.

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“…Several compounds contain two phenolic rings that mimic the A-and D-rings of E 2 (Table 1). Accordingly, these ligands adopt a binding mode reminiscent of that used by E 2 , with the two phenol groups hydrogenbonded to the polar residues of the LBP, as illustrated by BP-2 [24] ( Figure 2B) and the phytoestrogen resveratrol [27] (RES, Figure 2C). The remaining contacts essentially involve van der Waals interactions, the number of which varies from one compound to another and accounts for the variation in binding affinities of the ligands.…”

Section: The Estrogen Receptors and Their Environmental Ligandsmentioning

confidence: 99%

“…In this review, we describe the mechanisms by which compounds that are structurally divergent from natural estrogens and that belong to families representing pollutants bind to ERs and impact their signaling pathways. [29] 2QXM [87] 3UU7 [29] 3UUA [29] 3UUC [29] 4MG8 [24] 4TUZ [24] 4MG7 [24] 4MG9 [24] 4TV1 ERβ 3OLS [89] Estradiol (E 2 ) [87] 2QSE [87] 4MGB [24] 4MGD [24] 4MGC [24] 4MG5 [24] 4MGA [24] 4MG6 [24] 4PP6 [27] 3ERD [88] ERβ 1X7J [86] / 1QKM [26] www.nature.com/aps Delfosse V et al Acta Pharmacologica Sinica npg (eg, genistein and ferutinine) and myco-estrogens (eg, zearalenone) are found in plants and fungi, whereas synthetic estrogens comprise both pharmaceuticals, such as ethinylestradiol (EE2; an active component of contraceptive pills) or diethylstilbestrol (DES; used until the 1970s to prevent miscarriage in women with high risk pregnancies) and a variety of industrial chemicals, such as alkylphenols, bisphenols, and their halogenated derivatives, parabens, phthalates, or benzophenones. The pharmaceuticals and some natural estrogens are the ligands that bind to ERs with the highest affinity, with dissociation constant (K d ) values in the (sub)nanomolar range [24] .…”

Section: The Estrogen Receptors and Their Environmental Ligandsmentioning

confidence: 99%

A structural perspective on nuclear receptors as targets of environmental compounds

Delfosse¹,

Maire²,

Balaguer³

et al. 2014

Acta Pharmacol Sin

107

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Nuclear receptors (NRs) are members of a large superfamily of evolutionarily related transcription factors that control a plethora of biological processes. NRs orchestrate complex events such as development, organ homeostasis, metabolism, immune function, and reproduction. Approximately one-half of the 48 human NRs have been shown to act as ligand-regulated transcription factors and respond directly to a large variety of endogenous hormones and metabolites that are generally hydrophobic and small in size (eg, retinoic acid or estradiol). The second half of the NR family comprises the so-called orphan receptors, for which regulatory ligands are still unknown or may not exist despite the presence of a C-terminal ligand-binding domain, which is the hallmark of all NRs. Several chemicals released into the environment (eg, bisphenols, phthalates, parabens, etc) share some physicochemical properties with natural ligands, allowing them to bind to NRs and activate or inhibit their action. Collectively referred to as endocrine disruptors or endocrine-disrupting chemicals (EDCs), these environmental pollutants are highly suspected to cause a wide range of developmental, reproductive, neurological, or metabolic defects in humans and wildlife. Crystallographic studies are revealing unanticipated mechanisms by which chemically diverse EDCs interact with the ligand-binding domain of NRs. These studies thereby provide a rational basis for designing novel chemicals with lower impacts on human and animal health. In this review, we provide a structural and mechanistic view of endocrine disrupting action using estrogen receptors α and β, (ERα/β), peroxisome proliferator activated receptor γ (PPARγ), and their respective environmental ligands as representative examples.

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Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Cited by 121 publications

References 98 publications

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

A structural perspective on nuclear receptors as targets of environmental compounds

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