Estrogen-related receptor-α

Target id: 622

Nomenclature: Estrogen-related receptor-α

Systematic Nomenclature: NR3B1

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.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 423 11q13 ESRRA estrogen-related receptor alpha 5
Mouse 422 19A Esrra estrogen related receptor, alpha 16
Rat 422 1q43 Esrra estrogen related receptor, alpha 1
Previous and Unofficial Names
ERRα
ESRL1
estrogen receptor-like 1
nuclear receptor subfamily 3 group B member 1
steroid hormone receptor ERR1
Estrra
Database Links
ChEMBL 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:  Human estrogen-related receptor alpha in complex with a synthetic inverse agonist
PDB Id:  2PJL
Ligand:  cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine
Resolution:  2.3Å
Species:  Human
References:  11
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
genistein Hs Agonist - - 18
[18]
biochanin A Hs Agonist - - 18
[18]
daidzein Hs Agonist - - 18
[18]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine Hs Inverse agonist 6.7 pIC50 11
pIC50 6.7 [11]
XCT790 Hs Antagonist 6.1 – 6.5 pIC50 22
pIC50 6.1 – 6.5 [22]
diethylstilbestrol Mm Antagonist 4.8 – 5.3 pIC50 19
pIC50 4.8 – 5.3 [19]
toxaphene Mm Antagonist - - 24
[24]
chlordane Mm Antagonist - - 24
[24]
View species-specific antagonist tables
Antagonist Comments
Toxaphene is a very complex, but reproducible mixture of at least 177 C10 polychloro derivatives, having an approximate overall empirical formula of C10-H10-Cl8. It is used as an insecticide and may reasonably be anticipated to be a carcinogen. Chlordan is a highly poisonous organochlorine insecticide. Both molecules have been shown to inhibit the transcriptional activities of ERR, probably by impairing its interactions with coactivators such as GRIP1 [24].
DNA Binding
Structure:  Monomer, Homodimer
HRE core sequence:  TNA AGGTCA
Response element:  Other DR, ERE
DNA Binding Comments
It was shown that both ERRs binds SFREs (SF1 Response Elements: TNA AGGTCA) and EREs (Estrogen Responsive Elements) in vitro and that ERR1 interact with these elements as a dimer. However, recent data clearly indicate that ERRs specifically bind SFRE and not ERE in vivo (V. Giguère, personal communication).
Co-binding Partners
Name Interaction Effect Reference
Estrogen receptor-α Physical, Functional 10,25
Co-binding Partners Comments
ERR alpha may play a role in the response of some genes to estrogen via heterodimerization with ERs. The relevance of this interaction in vivo is still a matter of debate.
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
PNRC2 Co-activator No Yes Yes 26
NCOA3 Co-activator - No Yes 23
NCOA2 Co-activator - No Yes 23
NCOA1 Co-activator - No Yes 23
PNRC1 Other - No - 27
PPARGC1A Co-activator No No Yes coexpressed with ERR&alpha 7-9,15
Main Target Genes
Name Species Effect Technique Comments References
ACADM Human Activated Transient transfection, EMSA, Other observed in all species studied 17
SPP1 Human Activated Transient transfection, EMSA observed in all species studied 21
THRA Human Activated Transient transfection, EMSA, Other 20
LTF Human Activated Transient transfection, EMSA, Footprint 25
APOA1 Human Activated ChIP, Transient transfection, other ERR alpha, in cooperation with PGC-1 , activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. 4
Tissue Distribution
Cerebellum, hippocampus, kidney, gut, heart, hypothalamus, liver, lung, reproductive tissues (uterus, vagina, cervix), HeLa cells, embryonic tissue (nervous system, muscles, epidermis, intestine and urogenital endodermis).
Species:  Human
Technique:  Immunohistology, Northern blot, Western blot, in situ hybridization and other
References:  2-3,5-6,10,16
Tissue Distribution Comments
NR3B1 expression is observed in both human and rodent systems (as 2.2 to 2.6 kb mRNAs). Interestingly, expression of ERRalpha displays a circadian rhythmicity in liver, bone and uterus.
Physiological Consequences of Altering Gene Expression
ERRalpha KO mice:-reduced body weight, resistant to high-fat diet induced obesity
Species:  Mouse
Tissue: 
Technique:  knock out
References:  14
Physiological Consequences of Altering Gene Expression Comments
ERRα null mice are viable, fertile and display no gross anatomical alterations, with the exception of and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. Interestingly, the mutant animals are resistant to a high-fat diet-induced obesity.
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0005666 abnormal adipose tissue physiology PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0000130 abnormal cancellous bone morphology PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0002118 abnormal lipid homeostasis PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0008396 abnormal osteoclast differentiation PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0001262 decreased body weight PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0000333 decreased bone marrow cell number PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0004993 decreased bone resorption PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0009289 decreased epididymal fat pad weight PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0009293 decreased inguinal fat pad weight PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0004985 decreased osteoclast cell number PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0005459 decreased percent body fat PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0009305 decreased retroperitoneal fat pad weight PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0009133 decreased white fat cell size PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0000240 extramedullary hematopoiesis PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0003960 increased lean body mass PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0004988 increased osteoblast cell number PMID: 20519122 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1346831  MP:0000679 increased percent water in carcass PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: C57BL/6
MGI:1346831  MP:0005659 increased resistance to diet-induced obesity PMID: 14585956 
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0009338 increased splenocyte number PMID: 20519122 
Esrratm1Dgen Esrratm1Dgen/Esrratm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1346831  MP:0002169 no abnormal phenotype detected
Esrratm1Vgi Esrratm1Vgi/Esrratm1Vgi
involves: 129S1/Sv * 129X1/SvJ
MGI:1346831  MP:0000067 osteopetrosis PMID: 20519122 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Obesity
Comments: 
References:  12
Disease:  Osteoporosis
Comments: 
References:  13

References

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1. Bonnelye E, Merdad L, Kung V, Aubin JE. (2001) The orphan nuclear estrogen receptor-related receptor alpha (ERRalpha) is expressed throughout osteoblast differentiation and regulates bone formation in vitro. J. Cell Biol.153 (5): 971-84. [PMID:11381083]

2. Bonnelye E, Vanacker JM, Dittmar T, Begue A, Desbiens X, Denhardt DT, Aubin JE, Laudet V, Fournier B. (1997) The ERR-1 orphan receptor is a transcriptional activator expressed during bone development. Mol. Endocrinol.11 (7): 905-16. [PMID:9178750]

3. Bonnelye E, Vanacker JM, Spruyt N, Alric S, Fournier B, Desbiens X, Laudet V. (1997) Expression of the estrogen-related receptor 1 (ERR-1) orphan receptor during mouse development. Mech. Dev.65 (1-2): 71-85. [PMID:9256346]

4. Carrier JC, Deblois G, Champigny C, Levy E, Giguère V. (2004) Estrogen-related receptor alpha (ERRalpha) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine. J. Biol. Chem.279 (50): 52052-8. [PMID:15466464]

5. Giguère V, Yang N, Segui P, Evans RM. (1988) Identification of a new class of steroid hormone receptors. Nature331 (6151): 91-4. [PMID:3267207]

6. Horard B, Rayet B, Triqueneaux G, Laudet V, Delaunay F, Vanacker JM. (2004) Expression of the orphan nuclear receptor ERRalpha is under circadian regulation in estrogen-responsive tissues. J. Mol. Endocrinol.33 (1): 87-97. [PMID:15291745]

7. Huss JM, Kopp RP, Kelly DP. (2002) Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J. Biol. Chem.277 (43): 40265-74. [PMID:12181319]

8. Huss JM, Torra IP, Staels B, Giguère V, Kelly DP. (2004) Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol. Cell. Biol.24 (20): 9079-91. [PMID:15456881]

9. Ichida M, Nemoto S, Finkel T. (2002) Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha). J. Biol. Chem.277 (52): 50991-5. [PMID:12397057]

10. Johnston SD, Liu X, Zuo F, Eisenbraun TL, Wiley SR, Kraus RJ, Mertz JE. (1997) Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol. Endocrinol.11 (3): 342-52. [PMID:9058380]

11. Kallen J, Lattmann R, Beerli R, Blechschmidt A, Blommers MJ, Geiser M, Ottl J, Schlaeppi JM, Strauss A, Fournier B. (2007) Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism. J. Biol. Chem.282 (32): 23231-9. [PMID:17556356]

12. Kamei Y, Lwin H, Saito K, Yokoyama T, Yoshiike N, Ezaki O, Tanaka H. (2005) The 2.3 genotype of ESRRA23 of the ERR alpha gene is associated with a higher BMI than the 2.2 genotype. Obes. Res.13 (10): 1843-4. [PMID:16286534]

13. Laflamme N, Giroux S, Loredo-Osti JC, Elfassihi L, Dodin S, Blanchet C, Morgan K, Giguère V, Rousseau F. (2005) A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women. J. Bone Miner. Res.20 (6): 938-44. [PMID:15883633]

14. Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V. (2003) Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol. Cell. Biol.23 (22): 7947-56. [PMID:14585956]

15. Schreiber SN, Knutti D, Brogli K, Uhlmann T, Kralli A. (2003) The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). J. Biol. Chem.278 (11): 9013-8. [PMID:12522104]

16. Shigeta H, Zuo W, Yang N, DiAugustine R, Teng CT. (1997) The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness. J. Mol. Endocrinol.19 (3): 299-309. [PMID:9460651]

17. Sladek R, Bader JA, Giguère V. (1997) The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol. Cell. Biol.17 (9): 5400-9. [PMID:9271417]

18. 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]

19. 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]

20. Vanacker JM, Bonnelye E, Delmarre C, Laudet V. (1998) Activation of the thyroid hormone receptor alpha gene promoter by the orphan nuclear receptor ERR alpha. Oncogene17 (19): 2429-35. [PMID:9824153]

21. Vanacker JM, Delmarre C, Guo X, Laudet V. (1998) Activation of the osteopontin promoter by the orphan nuclear receptor estrogen receptor related alpha. Cell Growth Differ.9 (12): 1007-14. [PMID:9869301]

22. Willy PJ, Murray IR, Qian J, Busch BB, Stevens WC, Martin R, Mohan R, Zhou S, Ordentlich P, Wei P, Sapp DW, Horlick RA, Heyman RA, Schulman IG. (2004) Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. Proc. Natl. Acad. Sci. U.S.A.101 (24): 8912-7. [PMID:15184675]

23. Xie G, Drachenberg C, Yamada M, Wess J, Raufman JP. (2005) Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors. Am J Physiol Gastrointest Liver Physiol289: G521-G529. [PMID:15933222]

24. Yang C, Chen S. (1999) Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Res.59 (18): 4519-24. [PMID:10493499]

25. Yang N, Shigeta H, Shi H, Teng CT. (1996) Estrogen-related receptor, hERR1, modulates estrogen receptor-mediated response of human lactoferrin gene promoter. J. Biol. Chem.271 (10): 5795-804. [PMID:8621448]

26. Zhou D, Chen S. (2001) PNRC2 is a 16 kDa coactivator that interacts with nuclear receptors through an SH3-binding motif. Nucleic Acids Res.29 (19): 3939-48. [PMID:11574675]

27. Zhou D, Quach KM, Yang C, Lee SY, Pohajdak B, Chen S. (2000) PNRC: a proline-rich nuclear receptor coregulatory protein that modulates transcriptional activation of multiple nuclear receptors including orphan receptors SF1 (steroidogenic factor 1) and ERRalpha1 (estrogen related receptor alpha-1). Mol. Endocrinol.14 (7): 986-98. [PMID:10894149]

How to cite this page

3B. Estrogen-related receptors: Estrogen-related receptor-α. Last modified on 23/10/2014. Accessed on 26/11/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=622.