Structural Insights into the Specificity of Ligand Binding and Coactivator Assembly by Estrogen-Related Receptor β

Yao, Benqiang; Zhang, Shuchi; Wei, Yijuan; Tian, Siyu; Zhou, Lu; Jin, Lihua; He, Ying; Xie, Wen; Li, Yong

doi:10.1016/j.jmb.2020.08.007

Cited by 12 publications

(8 citation statements)

References 49 publications

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“…It should be remembered that ERRs do not have any recognized substrate and that ERRα is constitutively active, i.e., it does not require the presence of a ligand to activate the transcription machinery [82,83]. Differently, ERRβ provided interesting results, but an induced fit modality had to be adopted in order to allow active site residues a certain flexibility (PDB ID 6lit [84]). NRG was the best scored, forming polar contacts with Glu250, Arg291, Tyr301, and Ala406, hydrophobic interactions with Phe410, Leu320, Leu243, Met281, Leu284, Ile288, and Ile324, and a π-π contact with Phe410 (Figure 7a).…”

Section: Flavonoids and Sex Steroids Hormones In Erα And Erβ And In Errα Errβ And Errγmentioning

confidence: 99%

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Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

et al. 2021

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Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17β-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERβ, ERRβ, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein–ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.

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Section: Flavonoids and Sex Steroids Hormones In Erα And Erβ And In Errα Errβ And Errγmentioning

confidence: 99%

“…Figure 7. Docking poses of NRG (a) and of LUT (b) in ERRβ (PDB ID 6lit[84]) and of NRG (c) in ERRγ. The protein is shown in transparent light green cartoon, the residues lining the binding site and the ligands are shown in capped sticks and colored light green and yellow, respectively.…”

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confidence: 99%

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

et al. 2021

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“…As discussed earlier, the AF-2 helix is important for co-activator binding, and binding of 4-OHT changes the conformation of the AF-2 helix. This conformational change blocks the binding of any NR-box co-activator peptides and represses the activity of ERRγ [ 16 , 53 , 54 ]. The observed betweenness centrality (C B ) of the residues and the difference in the betweenness centrality values (C Bd ) further identified residues that were critical for intra-residue signal transduction and functioning of ERRγ [ 16 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist

et al. 2023

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Estrogen-related receptor gamma (ERRγ), the latest member of the ERR family, does not have any known reported natural ligands. Although the crystal structures of the apo, agonist-bound, and inverse agonist-bound ligand-binding domain (LBD) of ERRγ have been solved previously, their dynamic behavior has not been studied. Hence, to explore the intrinsic dynamics of the apo and ligand-bound forms of ERRγ, we applied long-range molecular dynamics (MD) simulations to the crystal structures of the apo and ligand-bound forms of the LBD of ERRγ. Using the MD trajectories, we performed hydrogen bond and binding free energy analysis, which suggested that the agonist displayed more hydrogen bonds with ERRγ than the inverse agonist 4-OHT. However, the binding energy of 4-OHT was higher than that of the agonist GSK4716, indicating that hydrophobic interactions are crucial for the binding of the inverse agonist. From principal component analysis, we observed that the AF-2 helix conformation at the C-terminal domain was similar to the initial structures during simulations, indicating that the AF-2 helix conformation is crucial with respect to the agonist or inverse agonist for further functional activity of ERRγ. In addition, we performed residue network analysis to understand intramolecular signal transduction within the protein. The betweenness centrality suggested that few of the amino acids are important for residue signal transduction in apo and ligand-bound forms. The results from this study may assist in designing better therapeutic compounds against ERRγ associated diseases.

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Section: Regulation Of Estrogen-responsive Genes By Errsmentioning

confidence: 99%

“…Despite their sequence homology (36%) with ERs in the LBD, ERRs do not (or only very weakly) respond to estradiol (E2) and are constitutively active [18][19][20][21][22]. Their LBD interacts with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand and resumes an active conformation [18]. Since ERRs are identified using DBD of ER and the two receptors share high DBD domain similarities, all three members of the ERR family are able to bind to the half-site hexanucleotide repeat of the classical estrogen response element (ERE) that are recognized by ER [8].…”

Section: Regulation Of Estrogen-responsive Genes By Errsmentioning

confidence: 99%

Transcriptional Regulation by ERR and Its Role in NAFLD Pathogenesis

Hua¹,

Slarve²,

Datta³

et al. 2023

Non-Alcoholic Fatty Liver Disease - New Insight and Glance Into Disease Pathogenesis

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Members of estrogen-related receptors (ERRs) are orphan nuclear receptors (NRs) that play primary roles in mitochondrial biogenesis and bioenergetics. The ERRs regulate a range of cellular functions, including oxidative phosphorylation (OXPHOS) as well as glucose and lipid metabolism. ERRs are considered important targets for the treatment of metabolic diseases, particularly type II diabetes (T2D), insulin resistance (IR) and obesity. In this review, we will overview the transcriptional network regulated by the members of ERR transcriptional factors and elaborate on the regulation of ERR via its binding to PGC-1α, the primary co-activator of ERR as well as post-translational regulation of ERRs by upstream kinase signals. Recent development in ERR’s cellular function has identified lipid metabolism/lipogenesis as a process that ERR regulates, and this function significantly impacts metabolic syndrome. Here, we will focus on their roles in lipid metabolic regulation and discuss the in vivo functions of ERRs in the development of non-alcoholic fatty liver disease (NAFLD), a comorbid metabolic syndrome concurrent with T2D, IR as well as obesity. Finally, we will explore ERRs as potential therapeutic targets by discussing the ligands that serve as antagonist/agonists for ERRs as well as efforts that target DNA binding of ERR as a transcriptional factor.

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Structural Insights into the Specificity of Ligand Binding and Coactivator Assembly by Estrogen-Related Receptor β

Cited by 12 publications

References 49 publications

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist

Transcriptional Regulation by ERR and Its Role in NAFLD Pathogenesis

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