Structural and Functional Evidence for Ligand-Independent Transcriptional Activation by the Estrogen-Related Receptor 3

Greschik, Holger; Wurtz, Jean‐Marie; Sanglier, Sarah; Bourguet, William; Dorsselaer, Alain Van; Moras, Dino; Renaud, Jean‐Paul

doi:10.1016/s1097-2765(02)00444-6

Cited by 270 publications

(263 citation statements)

References 34 publications

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“…Because these receptors have very small ligand biding pockets, endogenous ligand discovery remains unlikely, although synthetic ligands have been developed and ERRα is blocked by diethylstilbestrol, while ERRβ and γ are blocked by tamoxifen (Coward et al 2001;Greschik et al 2002;Willy et al 2004). The activity of ERRs appears to be constitutive, with the ligand binding pocket stably arranged in an active conformation without ligand (Xie et al 1999;Greschik et al 2002;Greschik et al 2004). Because ERRα is widely expressed in adult tissues, especially in tissues that utilize or can utilize fatty acid β-oxidation, many studies have addressed its role in cellular energetics (Luo et al 2003).…”

Section: Errsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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Section: Errsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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“…Both vertebrate ERRs and invertebrate ERs are constitutively active and do not bind estradiol. The crystal structures of human ERRs [11][12][13][14] and a 3D model of octopus ER [33] indicates that their ligand-binding domains are too small to accommodate estradiol.…”

Section: Figure 1 Phylogenetic Analysis Of Invertebrate and Vertebramentioning

confidence: 99%

“…An explanation for the absence of steroid binding by ERRs came from analysis of the crystal structures of human ERRα [11,12] and ERRγ [13], which showed that the ligand binding site is too small to accommodate a steroid [11][12][13][14]. Unlike the ER, the ERR does not require a ligand to become transcriptionally active.…”

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confidence: 99%

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

Baker

2008

Biochemical and Biophysical Research Communications

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“…Despite their significant homology with ERs in the ligand binding domain (LBD), ERRs do not (or only very weakly) respond to estradiol (E2) (2,12). Furthermore, whereas ERs are ligand-activated receptors, ERRs are constitutively active (13)(14)(15)(16), and a structural study confirmed that the ERR␥ LBD can adopt a transcriptionally active conformation and interact with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand (12).…”

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confidence: 99%

Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity

Greschik

Flaig

Renaud

et al. 2004

Journal of Biological Chemistry

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The estrogen-related receptor (ERR) ␥ behaves as a constitutive activator of transcription. Although no natural ligand is known, ERR␥ is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERR␥ ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERR␥ results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the "activation helix" (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ER␣ LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERR␥ does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERR␥ and ER␣ reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERR␥ relative to ER␣. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERR␥ and reveal structural differences with ERs that explain why ERR␥ does not bind estradiol or raloxifene and will help to design new selective antagonists.The estrogen-related receptors ERR␣, 1 ERR␤, and ERR␥ (NR3B1, -2, and -3) (1) form a subfamily of orphan nuclear receptors that share significant amino acid homology with the estrogen receptors ER␣ and ER␤ (NR3A1 and -2) (2, 3). Because of the high conservation in the DNA binding domain, ERRs and ERs have overlapping DNA binding selectivity (4 -6) and, accordingly, may co-regulate target genes in tissues in which they are co-expressed. ERR subfamily members have for example been shown to modulate the expression of ER target genes in bone (7,8) or breast tissue (9, 10). Importantly, overexpression of ERR␣ and ERR␥ in samples from breast cancer patients correlates with unfavorable and favorable biomarkers, respectively (11). Therefore, these receptors might serve as prognostic markers themselves or even be targets for endocrine therapy in human breast cancer.Despite their significant homology with ERs in the ligand binding domain (LBD), ERRs do not (or only very weakly) respond to estradiol (E2) (2, 12). Furthermore, whereas ERs are ligand-activated receptors, ERRs are constitutively active (13-16), and a structural study confirmed that the ERR␥ LBD can adopt a transcriptionally active conformation and interact with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand (12). Together, these observations suggest that ERRs are ligand-independent activators of transcription whose activation potential may rather be determined by the presence of transcriptional coactivators (17)(18)(1...

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Structural and Functional Evidence for Ligand-Independent Transcriptional Activation by the Estrogen-Related Receptor 3

Cited by 270 publications

References 34 publications

Nuclear receptors, mitochondria and lipid metabolism

Nuclear receptors, mitochondria and lipid metabolism

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity

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