Molecular Basis for the Constitutive Activity of Estrogen-related Receptor α-1

Chen, Shiuan; Zhou, Dujin; Yang, Chun; Sherman, Mark A.

doi:10.1074/jbc.m102638200

Cited by 65 publications

(53 citation statements)

References 10 publications

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“…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). 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)(19)(20).…”

mentioning

confidence: 72%

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

120

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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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confidence: 72%

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

120

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“…In all three instances, we have demonstrated that mutations at relevant H3 and H5 positions markedly alter receptor sensitivity and͞or specificity, allowing us to create gain-of-function mutations for each of these receptors. Furthermore, an estrogen receptor ␣ bearing a substitution of phenylalanine for alanine at this precise H3 residue is constitutively active (23). Whereas loss-of-function mutations in NRs are relatively easy to devise, mutations which increase receptor activity are rare.…”

Section: Discussionmentioning

confidence: 99%

A critical role of helix 3–helix 5 interaction in steroid hormone receptor function

Zhang

Simisky²,

Tsai³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The ligand-binding domains of steroid hormone receptors possess a conserved structure with 12 ␣-helices surrounding a central hydrophobic core. On agonist binding, a repositioned helix 12 forms a pocket with helix 3 (H3) and helix 5 (H5), where transcriptional coactivators bind. The precise molecular interactions responsible for activation of these receptors remain to be elucidated. We previously identified a H3-H5 interaction that permits progesterone-mediated activation of a mutant mineralocorticoid receptor. We were intrigued to note that the potential for such interaction is widely conserved in the nuclear receptor family, indicating a possible functional significance. Here, we demonstrate via transcriptional activation studies in cell culture that alteration of residues involved in H3-H5 interaction consistently produces a gain of function in steroid hormone receptors. These data suggest that H3-H5 interaction may function as a molecular switch regulating the activity of nuclear receptors and suggest this site as a general target for pharmacologic intervention. Furthermore, they reveal a general mechanism for the creation of nuclear receptors bearing increased activity, providing a potentially powerful tool for the study of physiologic pathways in vivo. The precise molecular interactions that mediate these molecular events are beginning to be understood. Key residues within the LBDs of nuclear and steroid hormone receptors that interact with specific steroid functional groups have been identified, providing a structural basis for the steroid specificity of these receptors (2-8). For example, in the mineralocorticoid receptor (MR), it has been proposed that conserved residues in H3 and H5, Gln-776 and Arg-817, form hydrogen bonds with the 3-ketone group of steroid hormones to anchor aldosterone's A-ring, whereas conserved residues in H3 and helix 12, Asn-770 and Thr-945, mediate binding of the D-ring (2). Mineralocorticoid specificity of MR is thought to be provided, at least in part, by a hydrogen bond between Asn-770 on H3 and the C21-OH group of mineralocorticoids (2). Such ligand-receptor interactions have now been described for a number of different steroid͞nuclear hormone receptors (9). However, the relationship between ligand binding and receptor activation remains poorly understood, and events required beyond ligand binding for receptor activation have not been well defined.We previously demonstrated an interhelix interaction in MR via human genetic studies that markedly alters receptor activity (10). A single amino acid substitution in MR of leucine for serine at residue 810 in H5 (MR L810 ) causes severe early onset hypertension in humans with exacerbation during pregnancy. Transcriptional activation studies of the mutant MR L810 receptor indicated that antagonists of wild-type MR such as progesterone and spironolactone function as agonists of MR L810 , thus providing a pathophysiologic explanation for the observed worsening of hypertension during pregnancy (10). To better understand how a single a...

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“…The presence of a phenylalanine residue (Phe 328 on H3) in the ligand binding pocket (LBP) has been found to be essential for the constitutive activity of ERR␣, because its mutation to alanine abolishes constitutive activity (10). However, alanine residues are found at the corresponding positions of ERR␤ and ERR␥, indicating either different structural reasons for the apparent constitutive activity or a different mode of regulation for these other ERR isotypes.…”

mentioning

confidence: 88%

“…2B)). Phe 328 has been found to be crucial for the constitutive activity of ERR␣ (10). The substitutions Phe 382 /Tyr 326 and Gly 402 /Asn 346 do not significantly open the bottom part of the ERR␣ LBP with respect to ERR␥, because as a compensation the ERR␣ residues Phe 382 , Ala 393 , Gly 402 , and Leu 405 move closer together and thus practically fill the otherwise empty space.…”

Section: Structure Determination Of the Complex Between Err␣ Lbdmentioning

confidence: 99%

Evidence for Ligand-independent Transcriptional Activation of the Human Estrogen-related Receptor α (ERRα)

Kallen¹,

Schlaeppi

Bitsch³

et al. 2004

Journal of Biological Chemistry

197

109

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The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor ␣ (ERR␣, NR3B1) complexed with a coactivator peptide from peroxisome proliferator-activated receptor coactivator-1␣ (PGC-1␣) reveals a transcriptionally active conformation in the absence of a ligand. This is the first x-ray structure of ERR␣ LBD, solved to a resolution of 2.5 Å, and the first structure of a PGC-1␣ complex. The putative ligand binding pocket (LBP) of ERR␣ is almost completely occupied by side chains, in particular with the bulky side chain of Phe 328 (corresponding to Ala 272 in ERR␥ and Ala 350 in estrogen receptor ␣). Therefore, a ligand of a size equivalent to more than ϳ4 carbon atoms could only bind in the LBP, if ERR␣ would undergo a major conformational change (in particular the ligand would displace H12 from its agonist position). The x-ray structure thus provides strong evidence for ligand-independent transcriptional activation by ERR␣. The interactions of PGC-1␣ with ERR␣ also reveal for the first time the atomic details of how a coactivator peptide containing an inverted LXXLL motif (namely a LLXYL motif) binds to a LBD. In addition, we show that a PGC-1␣ peptide containing this nuclear box motif from the L3 site binds ERR␣ LBD with a higher affinity than a peptide containing a steroid receptor coactivator-1 motif and that the affinity is further enhanced when all three leucine-rich regions of PGC-1␣ are present.Nuclear hormone receptors (NRs) 1 are transcription factors that control essential developmental and physiological pathways (1). Although the transcriptional activity of NRs is often regulated by specific ligands, several members of the superfamily have no known natural ligands and are therefore referred to as orphan NRs (2). Estrogen-related receptor ␣ (ERR␣; NR3B1) was the first orphan NR to be identified on the basis of its similarity with estrogen receptor ␣ (ER␣; NR3A1) (3). ERR␣ and its relatives ERR␤ (NR3B2) and ERR␥ (NR3B3) form a small family of orphan NRs that are evolutionarily related to the estrogen receptors ER␣ and ER␤. ERRs preferentially bind to DNA sites composed of a single half-site preceded by three nucleotides with the consensus sequence TNAAGGTCA, referred to as an ERR response element. It has been shown that ERR␣ also efficiently binds to estrogen response elements and that these receptors share common target genes (4). This observation was further supported by studies demonstrating cross-talk between the ER and ERR pathways (reviewed in Ref. 5). The most striking feature observed in the phenotype of mice lacking ERR␣ is their resistance to high fat diet-induced obesity and the impaired activity of enzymes implicated in lipid metabolism. This finding led to the hypothesis that ERR␣ could be implicated in obesity or metabolic diseases (6). A function of ERR␣ on bone metabolism has also been suggested (7,8). Finally, recent publications show that ERR␣ and ERR␥ are associated with biomarkers of breast cancer and further emphasize the importance of ER-ERR cross-talk (9...

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Molecular Basis for the Constitutive Activity of Estrogen-related Receptor α-1

Cited by 65 publications

References 10 publications

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

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

A critical role of helix 3–helix 5 interaction in steroid hormone receptor function

Evidence for Ligand-independent Transcriptional Activation of the Human Estrogen-related Receptor α (ERRα)

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