Nomenclature: Estrogen-related receptor-γ

Systematic Nomenclature: NR3B3

Family: 3B. Estrogen-related receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 458 1q41 ESRRG estrogen-related receptor gamma 3,9
Mouse 435 1H5 Esrrg estrogen-related receptor gamma 9
Rat 435 13q26 Esrrg estrogen-related receptor gamma 13
Previous and Unofficial Names
ERR3
ERRγ
ESRL3
estrogen-related receptor γ
estrogen receptor-like 3
errg
estrogen receptor-related protein 3
estrogen-related receptor gamma
nuclear receptor subfamily 3 group B member 3
estrogen-related receptor 3
NR3B3
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Estrogen-related receptor gamma:-Ligand Binding Domain
PDB Id:  2GPU
Ligand:  4-hydroxy​tamoxifen
Resolution:  1.7Å
Species:  Human
References:  17
Natural/Endogenous Ligands
Comments: Orphan
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
DY131 Hs Agonist 6.2 pIC50 18,20
pIC50 6.2 [18,20]
GSK4716 Hs Agonist 5.7 pIC50 20
pIC50 5.7 [20]
genistein Hs Agonist - - 14
[14]
5,7-dihydroxy-4'-methoxyisoflavone Hs Agonist - - 14
[14]
7,4'-dihydroxyisoflavone Hs Agonist - - 14
[14]
Agonist Comments
The identification of the flavinoids compounds as ERRα agonist is based on cell transfection reporter assay and on mammalian two hibryd assays (PNRC2 induced recruitment). DY131 selectively activates ERRβ and γ. GSK4716 and GSK9089 binding affinity were measured by FRET.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
4-hydroxy​tamoxifen Hs Antagonist 7.5 pKd 2
pKd 7.5 [2]
diethylstilbestrol Hs Antagonist 4.8 – 5.3 pIC50 2,16
pIC50 4.8 – 5.3 [2,16]
DNA Binding
Structure:  Monomer, Homodimer
HRE core sequence:  TNA AGGTCA
Response element:  DR3, ERE, Other - see comments
DNA Binding Comments
ERRγ was shown to bind to the ERE as well as to the SFRE (SF1 Response Elements: TNA AGGTCA) and EREs, in vitro. Data suggest that ERR interaction with EREs does not occur in vivo (V. Giguère, personal communication). Importantly, ERRγ homodimerization seems to enhance its transcriptional activity [10].
Co-binding Partners
Name Interaction Effect Reference
DAX1 Physical, Functional DAX-1 inhibited PGC-1α mediated ERRγ transactivation, via competition between these two factors for the AF-2 binding domain. 12
SHP Physical, Functional SHP interaction with ERRγ inhibits its transcriptional activity 13
Calmodulin Physical, Functional Calmodulin and ERRγ interact in vitro in Ca2+ dependent manner and transient transfection analysis revealed a Ca2+-influx-dependent ERRγ-mediated transcriptional activation of a luciferase reporter gene. 7
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
PNRC2 Co-activator No Yes Yes 6
PPARGC1A Co-activator No No Yes 8
PPARGC1B Co-activator No No Yes 8
NCOA1 Co-activator No No Yes 4
TLE1 Co-activator - No - 6
Main Co-regulators Comments
TLE1 previously known as a corepressor, interacts with ERRγ AF-1 and acts as a coactivator.
Main Target Genes
Name Species Effect Technique Comments References
NR3B1 Human Activated ChIP, Transient transfection, EMSA, Other ERRγ activates ERRα expression via a conserved multi-hormone response element. 11
MAOA Human Activated ChIP, Transient transfection, EMSA, Other 19
MOAB Human Activated ChIP, Transient transfection, EMSA 19
Nr0b1 Mouse Activated ChIP, Transient transfection, EMSA 12
Tissue Distribution
Brain, kidney, testis, lung, adrenal gland, pancreas, placenta, bone marrow, heart
Species:  Human
Technique:  Northern-RT-PCR, in situ, Western, immunohistology, other
References:  1,3,5,9
Tissue Distribution Comments
Similar patterns seen in mice. And different studies are not in accordance for the expression in heart but this may be linked to the differential expression of transcripts coding for specific isoforms. Some studies have reported an absence of expression in 7 days post coitum mouse embryos and a high expression at 11, 15 and 17 days. This suggests that in contrast to ERRα and ERRβ, ERRγ is not expressed during early embryogenesis.
Physiological Consequences of Altering Gene Expression
Knock-out mice: homozygous do not survive to weaning, heterozygous exhibit an increase in overall startle amplitude, indicating a possible hypersensitivity to sound-induced motor reflex in these mice.
Species:  Mouse
Tissue: 
Technique:  Knock Out
References: 
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0009642 abnormal blood homeostasis PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0003137 abnormal impulse conducting system conduction PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0006036 abnormal mitochondrial physiology PMID: 17618853 
Esrrg+|Esrrgtm1Rev Esrrgtm1Rev/Esrrg+
various
MGI:1347056  MP:0006036 abnormal mitochondrial physiology PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0004215 abnormal myocardial fiber physiology PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0009546 absent gastric milk in neonates PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0010636 bundle branch block PMID: 17618853 
Esrrg+|Esrrgtm1Rev Esrrgtm1Rev/Esrrg+
various
MGI:1347056  MP:0010636 bundle branch block PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0009674 decreased birth weight PMID: 17618853 
Esrrg+|Esrrgtm1Dgen Esrrgtm1Dgen/Esrrg+
involves: 129P2/OlaHsd * C57BL/6
MGI:1347056  MP:0005604 hyperekplexia
Esrrgtm1Dgen Esrrgtm1Dgen/Esrrgtm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1347056  MP:0002082 postnatal lethality PMID: 19965931 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0002082 postnatal lethality PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
involves: C57BL/6
MGI:1347056  MP:0002082 postnatal lethality PMID: 19965931 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0010392 prolonged QRS complex duration PMID: 17618853 
Esrrg+|Esrrgtm1Rev Esrrgtm1Rev/Esrrg+
various
MGI:1347056  MP:0010392 prolonged QRS complex duration PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0003233 prolonged QT interval PMID: 17618853 
Esrrgtm1Rev Esrrgtm1Rev/Esrrgtm1Rev
various
MGI:1347056  MP:0010570 prolonged ST segment PMID: 17618853 
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  ERRγ3
Protein accession: 
References:  15
Type:  Splice variant
Species:  Human
Description:  ERRγ2 variant (differs from ERRγ1 by 23 N-terminal residues).
Protein accession: 
References:  15

REFERENCES

1. Chen F, Zhang Q, McDonald T, Davidoff MJ, Bailey W, Bai C, Liu Q, Caskey CT. (1999) Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. Gene228 (1-2): 101-9. [PMID:10072763]

2. Coward P, Lee D, Hull MV, Lehmann JM. (2001) 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc. Natl. Acad. Sci. U.S.A.98 (15): 8880-4. [PMID:11447273]

3. Eudy JD, Yao S, Weston MD, Ma-Edmonds M, Talmadge CB, Cheng JJ, Kimberling WJ, Sumegi J. (1998) Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. Genomics50 (3): 382-4. [PMID:9676434]

4. Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP. (2002) Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol. Cell9 (2): 303-13. [PMID:11864604]

5. Heard DJ, Norby PL, Holloway J, Vissing H. (2000) Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. Mol. Endocrinol.14 (3): 382-92. [PMID:10707956]

6. Hentschke M, Borgmeyer U. (2003) Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma. Biochem. Biophys. Res. Commun.312 (4): 975-82. [PMID:14651967]

7. Hentschke M, Schulze C, Süsens U, Borgmeyer U. (2003) Characterization of calmodulin binding to the orphan nuclear receptor Errgamma. Biol. Chem.384 (3): 473-82. [PMID:12715898]

8. Hentschke M, Süsens U, Borgmeyer U. (2002) PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma. Biochem. Biophys. Res. Commun.299 (5): 872-9. [PMID:12470660]

9. Hong H, Yang L, Stallcup MR. (1999) Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3. J. Biol. Chem.274 (32): 22618-26. [PMID:10428842]

10. Huppunen J, Aarnisalo P. (2004) Dimerization modulates the activity of the orphan nuclear receptor ERRgamma. Biochem. Biophys. Res. Commun.314 (4): 964-70. [PMID:14751226]

11. Liu D, Zhang Z, Teng CT. (2005) Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element. J. Mol. Endocrinol.34 (2): 473-87. [PMID:15821111]

12. Park YY, Ahn SW, Kim HJ, Kim JM, Lee IK, Kang H, Choi HS. (2005) An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRgamma. Nucleic Acids Res.33 (21): 6756-68. [PMID:16314306]

13. Razzaque MA, Masuda N, Maeda Y, Endo Y, Tsukamoto T, Osumi T. (2004) Estrogen receptor-related receptor gamma has an exceptionally broad specificity of DNA sequence recognition. Gene340 (2): 275-82. [PMID:15475169]

14. Suetsugi M, Su L, Karlsberg K, Yuan YC, Chen S. (2003) Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol. Cancer Res.1 (13): 981-91. [PMID:14638870]

15. Süsens U, Hermans-Borgmeyer I, Borgmeyer U. (2000) Alternative splicing and expression of the mouse estrogen receptor-related receptor gamma. Biochem. Biophys. Res. Commun.267 (2): 532-5. [PMID:10631096]

16. Tremblay GB, Kunath T, Bergeron D, Lapointe L, Champigny C, Bader JA, Rossant J, Giguère V. (2001) Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta. Genes Dev.15 (7): 833-8. [PMID:11297507]

17. Wang L, Zuercher WJ, Consler TG, Lambert MH, Miller AB, Orband-Miller LA, McKee DD, Willson TM, Nolte RT. (2006) X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation. J. Biol. Chem.281 (49): 37773-81. [PMID:16990259]

18. Yu DD, Forman BM. (2005) Identification of an agonist ligand for estrogen-related receptors ERRbeta/gamma. Bioorg. Med. Chem. Lett.15 (5): 1311-3. [PMID:15713377]

19. Zhang Z, Chen K, Shih JC, Teng CT. (2006) Estrogen-related receptors-stimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors. Mol. Endocrinol.20 (7): 1547-61. [PMID:16484337]

20. Zuercher WJ, Gaillard S, Orband-Miller LA, Chao EY, Shearer BG, Jones DG, Miller AB, Collins JL, McDonnell DP, Willson TM. (2005) Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma. J. Med. Chem.48 (9): 3107-9. [PMID:15857113]

To cite this database page, please use the following:

3B. Estrogen-related receptors: Estrogen-related receptor-γ. Last modified on 13/12/2013. Accessed on 01/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=624.

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