ESRRG

Summary

ESRRG (estrogen related receptor gamma, HGNC:3474) is a protein-coding gene on chromosome 1q41, encoding Estrogen-related receptor gamma (P62508). Orphan receptor that acts as a transcription activator in the absence of bound ligand.

This gene encodes a member of the estrogen receptor-related receptor (ESRR) family, which belongs to the nuclear hormone receptor superfamily. All members of the ESRR family share an almost identical DNA binding domain, which is composed of two C4-type zinc finger motifs. The ESRR members are orphan nuclear receptors; they bind to the estrogen response element and steroidogenic factor 1 response element, and activate genes controlled by both response elements in the absence of any ligands. The ESRR family is closely related to the estrogen receptor (ER) family. They share target genes, co-regulators and promoters, and by targeting the same set of genes, the ESRRs seem to interfere with the ER-mediated estrogen response in various ways. It has been reported that the family member encoded by this gene functions as a transcriptional activator of DNA cytosine-5-methyltransferases 1 (Dnmt1) expression by direct binding to its response elements in the DNMT1 promoters, modulates cell proliferation and estrogen signaling in breast cancer, and negatively regulates bone morphogenetic protein 2-induced osteoblast differentiation and bone formation. Multiple alternatively spliced transcript variants have been identified, which mainly differ at the 5’ end and some of which encode protein isoforms differing in the N-terminal region.

Source: NCBI Gene 2104 — RefSeq curated summary.

At a glance

• GWAS associations: 37
• Clinical variants (ClinVar): 66 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Transcription factor: yes — 30 downstream targets (CollecTRI)
• MANE Select transcript: NM_001438

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3474
Approved symbol	ESRRG
Name	estrogen related receptor gamma
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	NR3B3, ERRg, ERR-gamma
Ensembl gene	ENSG00000196482
Ensembl biotype	protein_coding
OMIM	602969
Entrez	2104

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 19 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000359162, ENST00000360012, ENST00000361395, ENST00000361525, ENST00000366937, ENST00000366938, ENST00000366940, ENST00000391890, ENST00000408911, ENST00000459825, ENST00000459955, ENST00000463665, ENST00000469486, ENST00000469913, ENST00000471371, ENST00000475275, ENST00000477799, ENST00000481543, ENST00000487276, ENST00000488947, ENST00000493603, ENST00000493748, ENST00000586199, ENST00000616180, ENST00000673908

RefSeq mRNA: 20 — MANE Select: NM_001438 NM_001134285, NM_001243505, NM_001243506, NM_001243507, NM_001243509, NM_001243510, NM_001243511, NM_001243512, NM_001243513, NM_001243514, NM_001243515, NM_001243518, NM_001243519, NM_001350122, NM_001350123, NM_001350124, NM_001350125, NM_001438, NM_206594, NM_206595

CCDS: CCDS1517, CCDS41468, CCDS58060, CCDS58061

Canonical transcript exons

ENST00000408911 — 7 exons

Exon	Start	End
ENSE00001409682	216503251	216507183
ENSE00001586839	216564219	216564380
ENSE00001626361	216650973	216651089
ENSE00003570231	216677076	216677491
ENSE00003648022	216723244	216723429
ENSE00003682678	216567988	216568098
ENSE00003787984	216519152	216519421

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.91.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8021 / max 507.1653, expressed in 431 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17475	1.2978	193
17476	0.5061	145
17490	0.3029	143
17492	0.2513	104
17477	0.2042	85
17491	0.1670	93
17483	0.1441	61
17488	0.1424	72
17485	0.1298	56
17486	0.1158	64

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	97.91	gold quality
nephron tubule	UBERON:0001231	96.27	gold quality
endothelial cell	CL:0000115	94.34	gold quality
renal medulla	UBERON:0000362	94.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.17	gold quality
kidney epithelium	UBERON:0004819	92.13	gold quality
heart right ventricle	UBERON:0002080	91.29	gold quality
parotid gland	UBERON:0001831	90.60	gold quality
diaphragm	UBERON:0001103	90.36	gold quality
choroid plexus epithelium	UBERON:0003911	90.14	gold quality
biceps brachii	UBERON:0001507	90.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.82	gold quality
primary visual cortex	UBERON:0002436	89.24	gold quality
myocardium	UBERON:0002349	89.17	gold quality
renal glomerulus	UBERON:0000074	88.52	gold quality
placenta	UBERON:0001987	88.44	gold quality
metanephric glomerulus	UBERON:0004736	87.88	gold quality
kidney	UBERON:0002113	87.79	gold quality
left ventricle myocardium	UBERON:0006566	87.58	gold quality
cerebellar vermis	UBERON:0004720	87.38	gold quality
adult mammalian kidney	UBERON:0000082	86.26	gold quality
pigmented layer of retina	UBERON:0001782	86.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.78	gold quality
middle temporal gyrus	UBERON:0002771	85.68	gold quality
occipital lobe	UBERON:0002021	85.62	gold quality
deltoid	UBERON:0001476	85.37	gold quality
jejunal mucosa	UBERON:0000399	84.89	gold quality
metanephros	UBERON:0000081	84.48	gold quality
cardia of stomach	UBERON:0001162	83.41	gold quality
vastus lateralis	UBERON:0001379	83.35	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	65.30
E-HCAD-10	yes	13.05
E-ANND-3	yes	7.67
E-CURD-135	no	820.14

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

30 targets.

Target	Regulation
ACADM
ATF6	Unknown
BGLAP	Repression
CDKN1A	Activation
CDKN1B
CREB3L3
CREBZF
CRP
CYP19A1
DNASE1
DNMT1	Unknown
ESRRA	Unknown
ESRRG
GATA4
IBSP	Repression
MIR127	Activation
MIR206
MIR433	Activation
NOTCH1
NR0B1	Activation
NR0B2	Activation
NRIP1
PCK1
PDK4	Activation
PLK2	Unknown
PPARGC1A	Activation
PPARGC1B
SPP1
WDR5	Repression
YY1	Unknown

Upstream regulators (CollecTRI, top): ATF6, CREBZF, ESRRG, FOXC1, HIF1A, NCOA2, NR0B1, NR0B2, NR5A1, SIRT1

miRNA regulators (miRDB)

198 targeting ESRRG, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-6740-5P	100.00	65.64	932
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4514	99.99	67.10	1870

Literature-anchored findings (GeneRIF, showing 40)

• Transcriptional activation by ERR3 can be ligand-independent. (PMID:11864604)
• Not only PNRC2 but also the corepressor TLE1 functioned as ERRgamma coactivator in a reporter gene analysis (PMID:14651967)
• ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ERalpha transcription in prostatic cells. (PMID:15598686)
• Data demonstrate that the multi-hormone response element of the estrogen-related receptor-alpha (ERRalpha) gene is a target for ERRgamma transactivation, which is enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. (PMID:15821111)
• Up-regulation of estrogen-related receptor gamma is associated with endometrial adenocarcinoma (PMID:16681769)
• Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. (PMID:16990259)
• First evidence is provided that the nuclear receptor estrogen-related receptor gamma forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features. (PMID:17761695)
• Results clearly indicate that estrogen-related receptor gamma forms an appropriate structure presumably to adopt an unidentified endogenous ligand. (PMID:18005256)
• ERRGamma (estrogen-related receptor gamma ) mRNA levels decreased from normal vagina of the pre-menopausal women to atrophic vaginal tissue in post-menopausal women (PMID:18328649)
• Receptor estrogen-related receptors alpha, beta and gamma physically interact with HIF and stimulate HIF-induced transcription in tumor cells cultured under hypoxia. (PMID:18509053)
• The 2.0 A crystal structure of the 4-alpha-cumylphenol/ERRgamma complex clearly revealed that ERRgamma’s Leu345-beta-isopropyl plays a role in the tight binding of 4-alpha-cumylphenol and BPA, rotating in a back-and-forth induced-fit manner. (PMID:18582436)
• Kaempferol is an estrogen-related receptor gamma inverse agonist. (PMID:19171140)
• placenta expresses ERRgamma mRNA extremely highly; among the 3 ERRgamma protein isoforms, placenta exclusively expresses the type-1 isoform; results suggest that bisphenol A accumulates in the placenta by binding to ERRgamma (PMID:19304792)
• Single nucleotide polymorphisms in the estrogen-related receptor gamma is Associated with post-menopausal breast cancer women. (PMID:19415745)
• SMILE is a novel corepressor of ERRgamma, and SIRT1 has a role as a novel repressive mechanism for SMILE and ERRgamma inverse agonist (PMID:19690166)
• These results suggest involvement of ESRRgamma in the determination of bone density in women. (PMID:19821770)
• These results indicate that ERRalpha and ERRgamma are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity. (PMID:19822186)
• PPARalpha promoter variant impairs ERRA and ERRG dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes. (PMID:20838448)
• Estrogen-related receptor gamma modulates cell proliferation and estrogen signaling in breast cancer. (PMID:20883782)
• miR-378( *) inhibits the expression of two PGC-1beta partners, ERRgamma and GABPA, leading to a reduction in TCA cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation (PMID:20889127)
• Our study indicates that the AAAG tetranucleotide repeat polymorphism in ERR-gamma gene 5’ UTR region may be a new biomarker for genetic susceptibility to breast cancer. (PMID:21153485)
• Parkin degrades ESRRA, ESRRB and ESRRG to limit the expression of MAOA and MAOB. (PMID:21177257)
• Study provides evidence for nuclear receptor mediated regulation of Dnmt1 expression through ERRgamma and SHP crosstalk. (PMID:21459093)
• These novel findings identify ERRgamma as an O(2)-dependent transcription factor and HIF-1alpha target gene that serves a critical role in the induction of hCYP19 expression during human trophoblast differentiation. (PMID:21757507)
• Estrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling (PMID:21911493)
• Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1alpha/ERRgamma complex (PMID:22049338)
• Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is key regulator of hepatic gluconeogenesis (PMID:22549789)
• results suggest that Estrogen-Related Receptor gamma (ERRgamma) could be implicated in the energy metabolism regulation of human trophoblasts (PMID:22763271)
• Data show that the orphan nuclear receptor estrogen related receptor gamma (ERRgamma) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. (PMID:23050013)
• The relationship between ERRgamma and ERalpha status could be a predictive marker for the treatment of uterine endometrial cancer. (PMID:23051957)
• plays a role in maintenance of hearing in both humans and mice. (PMID:23540940)
• ERRGamma mediates oxygen-dependent expression of genes involved in human trophoblast differentiation, function, and vascular homeostasis. (PMID:23584901)
• The ESRRG gene is a novel target of miR-205 mediated RNA-interference. (PMID:23589079)
• Nuclear ANG directly binds to the ANG-Binding Sequence within ERRgamma of ERRgamma gene and inhibits ERRgamma transcription to promote breast cancer cell proliferation. (PMID:23977052)
• These findings demonstrate a novel ERRgamma/GATA4 signal cascade in the development of cardiac hypertrophy. (PMID:24083978)
• Iranian women with short AAAG repeat are at higher risk of breast cancer. (PMID:24125170)
• ERRgamma protein levels are affected by the activation state of ERK/mitogen-activated protein kinase, and mutation of consensus ERK target sites impairs ERRgamma-driven transcriptional activity and tamoxifen resistance. (PMID:24684682)
• Report estrogen-mediated cell kinetics and the role of oestrogen-related receptor gamma on biliary epithelial cells in the pathogenesis of primary biliary cirrhosis. (PMID:24687322)
• A role for ESRRG in maternal blood pressure homeostasis during pregnancy. (PMID:24725083)
• The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERRgamma. (PMID:24978476)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esrrga	ENSDARG00000004861
mus_musculus	Esrrg	ENSMUSG00000026610
rattus_norvegicus	Esrrg	ENSRNOG00000002593
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), ESR1 (ENSG00000091831), NR3C1 (ENSG00000113580), ESRRB (ENSG00000119715), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRA (ENSG00000173153)

Protein

Protein identifiers

Estrogen-related receptor gamma — P62508 (reviewed: P62508)

Alternative names: ERR gamma-2, Estrogen receptor-related protein 3, Nuclear receptor subfamily 3 group B member 3

All UniProt accessions (7): C9J0E3, C9J5W9, C9JNX5, C9JU32, P62508, F1D8R5, F1D8R6

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor that acts as a transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements. Induces the expression of PERM1 in the skeletal muscle.

Subunit / interactions. Homodimer. Binds TLE1, PNRC1 and PNRC2. Binds GRIP1. Interacts with NRIP1, NCOA1 and NCOR2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the heart, kidney, brain, lung, bone marrow, adrenal gland, trachea, spinal cord and thyroid gland.

Post-translational modifications. Acetylated by PCAF/KAT2 (in vitro). Sumoylation on Lys-40 is enhanced by phosphorylation at Ser-45 and represses transcriptional activity. Phosphorylation on Ser-45 enhances sumoylation on Lys-40 thus repressing transcriptional activity.

Miscellaneous. No physiological activating ligand is known for this orphan receptor, but 4-hydroxytamoxifen and diethylstilbestrol act as inverse agonists and deactivate ESRRG.

Similarity. Belongs to the nuclear hormone receptor family. NR3 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P62508-1	1, Long	yes
P62508-2	2, Short
P62508-3	3
P62508-4	4
P62508-5	5

RefSeq proteins (20): NP_001127757, NP_001230434, NP_001230435, NP_001230436, NP_001230438, NP_001230439, NP_001230440, NP_001230441, NP_001230442, NP_001230443, NP_001230444, NP_001230447, NP_001230448, NP_001337051, NP_001337052, NP_001337053, NP_001337054, NP_001429, NP_996317, NP_996318 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR003078	Retinoic_acid_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR024178	Est_rcpt/est-rel_rcp	Family
IPR027289	Oest-rel_rcp	Family
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050200	Nuclear_hormone_rcpt_NR3	Family

Pfam: PF00104, PF00105

UniProt features (57 total): helix 14, sequence conflict 9, strand 9, mutagenesis site 8, splice variant 4, zinc finger region 2, turn 2, compositionally biased region 2, chain 1, domain 1, sequence variant 1, DNA-binding region 1, region of interest 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6XXC	X-RAY DIFFRACTION	1.3
6XY5	X-RAY DIFFRACTION	1.3
6Y18	X-RAY DIFFRACTION	1.3
6Y3W	X-RAY DIFFRACTION	1.34
6Y1D	X-RAY DIFFRACTION	1.38
8B4Q	X-RAY DIFFRACTION	1.4
8BJG	X-RAY DIFFRACTION	1.4
8BJN	X-RAY DIFFRACTION	1.4
8BM5	X-RAY DIFFRACTION	1.4
6I65	X-RAY DIFFRACTION	1.5
9KNG	X-RAY DIFFRACTION	1.5
9KND	X-RAY DIFFRACTION	1.52
2E2R	X-RAY DIFFRACTION	1.6
6I66	X-RAY DIFFRACTION	1.6
9KNF	X-RAY DIFFRACTION	1.62
6I61	X-RAY DIFFRACTION	1.65
6I62	X-RAY DIFFRACTION	1.65
2GPU	X-RAY DIFFRACTION	1.7
2ZKC	X-RAY DIFFRACTION	1.7
6I67	X-RAY DIFFRACTION	1.75
2ZBS	X-RAY DIFFRACTION	1.8
9KNE	X-RAY DIFFRACTION	1.8
9KNC	X-RAY DIFFRACTION	1.9
6Y58	X-RAY DIFFRACTION	1.9
6I64	X-RAY DIFFRACTION	1.91
2GPO	X-RAY DIFFRACTION	1.95
6K3N	X-RAY DIFFRACTION	1.97
2ZAS	X-RAY DIFFRACTION	2
2P7G	X-RAY DIFFRACTION	2.1
8IFO	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62508-F1	76.66	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 45, 40

Mutagenesis-validated functional residues (8):

Position	Phenotype
38	no effect on transcriptional activity.
39	4-fold increase in transcriptional activity.
40	abolishes sumoylation. 7-fold increase in transcriptional activity.
41	no effect on transcriptional activity.
42	4-fold increase in transcriptional activity.
44	no effect on transcriptional activity.
45	abolishes sumoylation. increased transcriptional activity.
45	no change in sumoylation nor transcriptional activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 335 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, AAGCAAT_MIR137, TAATAAT_MIR126, GGTGTGT_MIR329, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, NKX25_02, TATTATA_MIR374, GCM_PPM1D, TGACCTY_ERR1_Q2, MEF2_02, FOXO1_01, AAAYRNCTG_UNKNOWN, AATGGAG_MIR136, CAGCTG_AP4_Q5

GO Biological Process (7): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), positive regulation of cold-induced thermogenesis (GO:0120162), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (16): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nuclear steroid receptor activity (GO:0003707), nuclear receptor activity (GO:0004879), steroid binding (GO:0005496), zinc ion binding (GO:0008270), estrogen response element binding (GO:0034056), identical protein binding (GO:0042802), AF-2 domain binding (GO:0050682), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
nuclear receptor-mediated signaling pathway	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
hormone-mediated signaling pathway	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
steroid hormone receptor signaling pathway	1
positive regulation of RNA biosynthetic process	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nuclear receptor activity	1
nuclear receptor-mediated steroid hormone signaling pathway	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
lipid binding	1
transition metal ion binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
protein binding	1
protein domain specific binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
DNA binding	1
cation binding	1
chromosome	1

Protein interactions and networks

STRING

1470 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESRRG	SLC7A1	P30825	931
ESRRG	PPARGC1B	Q86YN6	905
ESRRG	PNRC2	Q9NPJ4	854
ESRRG	TLE1	Q04724	789
ESRRG	PPARGC1A	Q9UBK2	779
ESRRG	NR0B2	Q15466	691
ESRRG	GPER1	Q99527	656
ESRRG	POU1F1	P28069	651
ESRRG	ACADM	P11310	610
ESRRG	USH2A	O75445	567
ESRRG	TXNDC9	O14530	558
ESRRG	ESRRA	P11474	558
ESRRG	NCOA1	Q15788	549
ESRRG	PPARA	Q07869	532
ESRRG	MYOCD	Q8IZQ8	520

IntAct

60 interactions, top by confidence:

A	B	Type	Score
ESRRG	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.720
ESRRG	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.720
PPARGC1A	ESRRG	psi-mi:“MI:0407”(direct interaction)	0.720
ESRRG	PPARGC1B	psi-mi:“MI:0915”(physical association)	0.660
SHTN1	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
SUMO1P1	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
NR0B1	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
DEUP1	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
ESRRG	NUP160	psi-mi:“MI:0915”(physical association)	0.560
KIFC3	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
ESRRG	DEUP1	psi-mi:“MI:0915”(physical association)	0.560
NUP160	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
ESRRG	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
ESRRG	NRIP1	psi-mi:“MI:0915”(physical association)	0.550
ESRRG	SUMO1	psi-mi:“MI:0566”(sumoylation reaction)	0.440
ESRRG	SUMO2	psi-mi:“MI:0566”(sumoylation reaction)	0.440
ESRRG	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (107): ESRRG (Two-hybrid), ESRRG (Two-hybrid), KIFC3 (Two-hybrid), MEOX2 (Two-hybrid), NUP160 (Two-hybrid), KIAA1598 (Two-hybrid), CCDC67 (Two-hybrid), SUMO1P1 (Two-hybrid), PSMC5 (Two-hybrid), NCOA1 (Two-hybrid), ESRRG (Co-localization), ESRRG (Reconstituted Complex), ESRRG (Affinity Capture-Western), ESRRG (Reconstituted Complex), HIF1A (Affinity Capture-Western)

ESM2 similar proteins: A2T929, F1QLY4, O00482, O09018, O42101, O95718, P11475, P19793, P22449, P24468, P28700, P28701, P28705, P31396, P41235, P43135, P48443, P49698, P49700, P49743, P51128, P51129, P54779, P62508, P62509, P62510, P79926, Q05343, Q06725, Q06726, Q0GFF6, Q0VC20, Q14541, Q5BJR8, Q5I7G2, Q5RAM2, Q5REL6, Q60632, Q61539, Q6DHP9

Diamond homologs: A2T928, A2T929, A4IIG7, O35507, O42295, O42450, O57606, O77245, O97716, P03373, P04625, P10276, P10826, P10827, P10828, P11416, P12813, P13631, P15204, P17671, P18113, P18115, P18117, P18119, P18514, P18515, P18516, P18911, P19793, P22448, P22605, P22736, P22829, P28699, P28700, P28701, P28702, P28704, P28705, P37242

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NR0B2	“down-regulates quantity by repression”	ESRRG	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription cofactors	5	60.7×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

66 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	38
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1070622	NC_000001.10:g.(?216348580)(216896641_?)del	Pathogenic
1199384	Single allele	Pathogenic
4530566	NM_001438.4(ESRRG):c.550C>T (p.Arg184Cys)	Pathogenic
523271	GRCh37/hg19 1q41(chr1:215829463-219225857)	Pathogenic
60080	GRCh38/hg38 1q41(chr1:216396695-217549806)x1	Pathogenic
60081	GRCh38/hg38 1q41(chr1:216518607-219827290)x1	Pathogenic
4530564	NM_001438.4(ESRRG):c.446A>G (p.Lys149Arg)	Likely pathogenic
4530565	NM_001438.4(ESRRG):c.539G>A (p.Cys180Tyr)	Likely pathogenic
4530567	NM_001438.4(ESRRG):c.1346T>G (p.Leu449Arg)	Likely pathogenic
4530568	NM_001438.4(ESRRG):c.1352dup (p.Leu451fs)	Likely pathogenic

SpliceAI

6998 predictions. Top by Δscore:

Variant	Effect	Δscore
1:216507179:GGAGT:G	acceptor_gain	1.0000
1:216507180:GAGT:G	acceptor_gain	1.0000
1:216507182:GT:G	acceptor_gain	1.0000
1:216507183:TC:T	acceptor_loss	1.0000
1:216507184:C:CC	acceptor_gain	1.0000
1:216507186:G:C	acceptor_gain	1.0000
1:216507186:G:GC	acceptor_gain	1.0000
1:216519420:GCCT:G	acceptor_loss	1.0000
1:216519421:CCTG:C	acceptor_loss	1.0000
1:216519422:C:G	acceptor_loss	1.0000
1:216519423:T:A	acceptor_loss	1.0000
1:216564352:C:CT	acceptor_gain	1.0000
1:216564355:C:CT	acceptor_gain	1.0000
1:216564356:A:T	acceptor_gain	1.0000
1:216567986:A:AC	donor_gain	1.0000
1:216567987:C:CC	donor_gain	1.0000
1:216567987:CATGG:C	donor_gain	1.0000
1:216650967:CCTTA:C	donor_loss	1.0000
1:216650968:CTTA:C	donor_loss	1.0000
1:216650969:TTACC:T	donor_loss	1.0000
1:216650970:TACCT:T	donor_loss	1.0000
1:216650971:A:C	donor_loss	1.0000
1:216650972:C:G	donor_loss	1.0000
1:216650972:CCTT:C	donor_gain	1.0000
1:216657104:T:A	donor_gain	1.0000
1:216677506:A:AC	acceptor_gain	1.0000
1:216677506:A:C	acceptor_gain	1.0000
1:216939710:A:T	acceptor_gain	1.0000
1:216507024:G:GA	donor_gain	0.9900
1:216507181:AGT:A	acceptor_gain	0.9900

AlphaMissense

3027 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:216506955:A:C	L454W	1.000
1:216506955:A:G	L454S	1.000
1:216506958:A:G	M453T	1.000
1:216506961:T:A	E452V	1.000
1:216506962:C:T	E452K	1.000
1:216506967:A:G	F450S	1.000
1:216506970:A:G	L449P	1.000
1:216506970:A:T	L449H	1.000
1:216506985:A:T	V444D	1.000
1:216507024:G:T	A431D	1.000
1:216507025:C:G	A431P	1.000
1:216507041:C:A	R425S	1.000
1:216507041:C:G	R425S	1.000
1:216507042:C:A	R425M	1.000
1:216507042:C:G	R425T	1.000
1:216507045:A:G	L424P	1.000
1:216507051:G:C	P422R	1.000
1:216507054:A:G	L421P	1.000
1:216507120:A:G	L399P	1.000
1:216507144:A:G	L391P	1.000
1:216507153:A:T	V388D	1.000
1:216519156:A:C	N376K	1.000
1:216519156:A:T	N376K	1.000
1:216519163:A:G	L374P	1.000
1:216519163:A:T	L374H	1.000
1:216519166:G:T	A373D	1.000
1:216519172:G:T	A371D	1.000
1:216519173:C:G	A371P	1.000
1:216519174:T:A	K370N	1.000
1:216519174:T:G	K370N	1.000

dbSNP variants (sampled 300 via entrez): RS1000000188 (1:216784938 G>C), RS1000000875 (1:216605981 C>G), RS1000006751 (1:216532799 C>T), RS1000011040 (1:217036827 G>A), RS1000020445 (1:216523503 T>C,G), RS1000025208 (1:217082791 T>G), RS1000025792 (1:216511979 T>G), RS1000027747 (1:216656303 G>A,T), RS1000029127 (1:216586183 A>C), RS1000032907 (1:216966971 T>C), RS1000044249 (1:216844701 C>A), RS1000046272 (1:216991172 C>A,T), RS1000049851 (1:216569407 T>C), RS1000052147 (1:217007500 A>G), RS1000055989 (1:216790818 C>T)

Disease associations

OMIM: gene MIM:602969 | disease phenotypes: MIM:614816

GenCC curated gene-disease

Mondo (4): Loeys-Dietz syndrome 4 (MONDO:0013897), movement disorder (MONDO:0005395), scoliosis (MONDO:0005392), premature menopause (MONDO:0001119)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0002650	Scoliosis

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000659_7	Optic nerve measurement (cup area)	7.000000e-06
GCST000960_2	Cardiac hypertrophy	1.000000e-07
GCST001066_7	Dialysis-related mortality	4.000000e-06
GCST001850_31	Major depressive disorder	9.000000e-06
GCST002001_7	Adverse response to chemotherapy (neutropenia/leucopenia) (all antimicrotubule drugs)	2.000000e-06
GCST002065_11	Alcohol consumption	7.000000e-06
GCST002308_1	Mean arterial pressure (alcohol consumption interaction)	9.000000e-07
GCST002711_3	Sleep duration	9.000000e-06
GCST003262_282	Post bronchodilator FEV1	8.000000e-07
GCST003264_795	Post bronchodilator FEV1/FVC ratio	4.000000e-07
GCST003992_28	Photic sneeze reflex	1.000000e-72
GCST004524_9	Energy expenditure (24h)	8.000000e-06
GCST004988_671	Breast cancer	4.000000e-09
GCST005316_315	Intelligence (MTAG)	1.000000e-08
GCST005576_16	Intracranial aneurysm	1.000000e-06
GCST005652_1	Cleft lip with or without cleft palate (maternal periconceptional vitamin use interaction)	6.000000e-08
GCST006269_1154	General cognitive ability	2.000000e-08
GCST006631_31	Nicotine dependence and major depression (severity of comorbidity)	3.000000e-06
GCST007324_92	Adventurousness	6.000000e-09
GCST007325_249	General risk tolerance (MTAG)	2.000000e-09
GCST007327_20	Smoking status (ever vs never smokers)	2.000000e-08
GCST008152_112	Weight	4.000000e-06
GCST008529_18	Tea consumption	1.000000e-07
GCST008857_1	Depressive symptom (anhedonia) (ordinal trait)	3.000000e-08
GCST009028_8	Adverse response to drug	5.000000e-07
GCST010002_353	Refractive error	3.000000e-08
GCST010796_4126	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_4127	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_4128	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST010796_4139	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0002503	cardiac hypertrophy
EFO:0005260	response to antimicrotubule agent
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004337	intelligence
EFO:0003959	cleft lip
EFO:0009116	vitamin supplement exposure measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0004338	body weight
EFO:0010091	tea consumption measurement
EFO:0009587	anhedonia measurement
EFO:0009658	adverse effect
EFO:0004327	electrocardiography
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009069	Movement Disorders	C10.228.662
D012600	Scoliosis	C05.116.900.800.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4245 (SINGLE PROTEIN), CHEMBL4523738 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 525,547 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL411	DIETHYLSTILBESTROL	4	353,912
CHEMBL83	TAMOXIFEN	4	171,635

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 3B. Estrogen-related receptors

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
4-hydroxytamoxifen	Inverse agonist	7.46	pKd
GSK5182	Inverse agonist	7.1	pIC50
DY131	Agonist	6.2	pIC50
GSK4716	Agonist	5.7	pIC50
diethylstilbestrol	Antagonist	5.3	pIC50

Binding affinities (BindingDB)

18 measured of 29 human assays (29 total across all organisms); most potent 18 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[(1Z)-4-azido-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl]phenol	IC50	1 nM
4-[(1Z)-4-chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl]phenol	IC50	4 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-5-(methylsulfanyl)-2-phenylpent-1-en-1-yl]phenol	IC50	10 nM
4-[(1Z)-5-azido-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylpent-1-en-1-yl]phenol	IC50	13 nM
[3H]4-OHT	IC50	21 nM
(5Z)-6-{4-[2-(dimethylamino)ethoxy]phenyl}-6-(4-hydroxyphenyl)-5-phenylhex-5-enenitrile	IC50	25 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-6-hydroxy-2-phenylhex-1-en-1-yl]phenol	IC50	79 nM
4-[(1Z)-5-chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylpent-1-en-1-yl]phenol	IC50	100 nM
GSK9089	EC50	130 nM
(4Z)-5-{4-[2-(dimethylamino)ethoxy]phenyl}-5-(4-hydroxyphenyl)-4-phenylpent-4-enenitrile	IC50	200 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-en-1-yl]phenol	IC50	250 nM
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-5-hydroxy-2-phenylpent-1-en-1-yl]phenol	IC50	320 nM
N’-[(1E)-1-[4-(diethylamino)phenyl]ethylidene]-4-hydroxybenzohydrazide	EC50	500 nM
4-amino-N’-[(1E)-[4-(diethylamino)phenyl]methylidene]benzohydrazide	EC50	630 nM
Bisphenol A (BPA)	IC50	670 nM	US-9688816: Polyetherimide compositions and methods for the manufacture and use thereof
GSK4716	EC50	1300 nM
N’-[(1E)-[4-(diethylamino)phenyl]methylidene]benzohydrazide	EC50	1600 nM
4-alpha-Cumylphenol	IC50	9800 nM	US-9688816: Polyetherimide compositions and methods for the manufacture and use thereof

ChEMBL bioactivities

327 potent at pChembl≥5 of 329 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.31	IC50	4.91	nM	BISPHENOL A
8.30	IC50	5	nM	CHEMBL203472
8.26	Kd	5.5	nM	BISPHENOL A
8.22	IC50	6	nM	CHEMBL4436391
7.96	IC50	11	nM	CHEMBL2137046
7.89	IC50	13	nM	CHEMBL2137046
7.89	IC50	13	nM	4-HYDROXYTORMIFENE
7.89	IC50	13	nM	CHEMBL4741828
7.82	EC50	15	nM	CHEMBL2137046
7.77	IC50	17	nM	CHEMBL4437929
7.77	IC50	17	nM	CHEMBL4598385
7.75	IC50	18	nM	CHEMBL4437929
7.75	IC50	18	nM	CHEMBL4580171
7.75	IC50	18	nM	CHEMBL4579002
7.70	IC50	20	nM	CHEMBL3961676
7.70	IC50	20	nM	CHEMBL2137046
7.70	IC50	20	nM	CHEMBL4451327
7.70	IC50	20	nM	CHEMBL4757503
7.70	IC50	20	nM	CHEMBL4597874
7.68	IC50	21	nM	CHEMBL4541589
7.68	IC50	21	nM	CHEMBL4746616
7.60	IC50	25	nM	CHEMBL4580171
7.60	IC50	25	nM	CHEMBL4596569
7.58	IC50	26	nM	CHEMBL4472718
7.58	IC50	26	nM	CHEMBL4744529
7.58	IC50	26	nM	CHEMBL4803014
7.58	IC50	26	nM	CHEMBL4598385
7.58	IC50	26	nM	CHEMBL5829633
7.58	IC50	26	nM	CHEMBL4802584
7.58	IC50	26	nM	CHEMBL4597635
7.58	IC50	26	nM	CHEMBL4596092
7.57	IC50	27	nM	CHEMBL4443694
7.57	IC50	27	nM	CHEMBL4595377
7.55	IC50	28	nM	CHEMBL4585424
7.55	IC50	28	nM	CHEMBL4595194
7.54	IC50	29	nM	CHEMBL6044782
7.52	IC50	30	nM	CHEMBL4791981
7.52	IC50	30	nM	CHEMBL4793030
7.52	IC50	30	nM	CHEMBL4803014
7.50	IC50	32	nM	CHEMBL4597398
7.48	IC50	33	nM	CHEMBL4579002
7.47	IC50	34	nM	CHEMBL4792390
7.47	IC50	34	nM	CHEMBL4803014
7.47	IC50	34	nM	CHEMBL4803828
7.46	IC50	35	nM	CHEMBL4451327
7.46	IC50	35	nM	CHEMBL4597874
7.40	IC50	40	nM	CHEMBL4436391
7.40	IC50	40	nM	CHEMBL4597043
7.38	IC50	42	nM	CHEMBL5740468
7.38	IC50	42	nM	CHEMBL4803772

PubChem BioAssay actives

279 with measured affinity, of 709 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[2-(4-hydroxyphenyl)propan-2-yl]phenol	1464223: Binding affinity to human ERRgamma	ic50	0.0049	uM
4-[(Z)-4-azido-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1798194: Radioligand Displacement Assay from Article 10.1016/j.bmcl.2005.11.030: “Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.”	ic50	0.0050	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0060	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1799022: Radioligand Displacement Assay from Article 10.1016/j.bbrc.2008.06.050: “ERRgamma tethers strongly bisphenol A and 4-alpha-cumylphenol in an induced-fit manner.”	ic50	0.0103	uM
4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1499723: Antagonist activity at ERRgamma (unknown origin) assessed as inhibition of co-activator peptide recruitment by TR-FRET assay	ic50	0.0110	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-yl-3,6-dihydro-2H-pyridin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0130	uM
4-[(Z)-4-chloro-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1798194: Radioligand Displacement Assay from Article 10.1016/j.bmcl.2005.11.030: “Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.”	ic50	0.0130	uM
4-(2-phenylpropan-2-yl)phenol	1799022: Radioligand Displacement Assay from Article 10.1016/j.bbrc.2008.06.050: “ERRgamma tethers strongly bisphenol A and 4-alpha-cumylphenol in an induced-fit manner.”	ic50	0.0139	uM
(Z)-5-(4-methylphenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0170	uM
(Z)-5-[4-(4-ethylpiperazin-1-yl)phenyl]-5-(4-methylphenyl)-4-phenylpent-4-en-1-ol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0180	uM
(E)-5-(3-bromophenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0180	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1317925: Inhibition of fluorescien-conjugated coactivator PGC1a binding to GST-tagged human ERRgamma LBD after 1 hr by TR-FRET assay	ic50	0.0200	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol;dihydrochloride	1614397: Inverse agonist activity at CMX-gal4-fused ERRgamma (unknown origin) transfected in human AD293 cells co-expressing CMV-beta galactosidase assessed as effect on beta-galactosidase activity after 24 hrs by luciferase reporter gene assay	ic50	0.0200	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0200	uM
4-[(Z)-5-hydroxy-1-[4-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0200	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0210	uM
4-[(E)-2-(2,4-difluorophenyl)-5-hydroxy-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0210	uM
(Z)-5-(4-methylphenyl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-4-phenylpent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0260	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;dihydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0260	uM
(Z)-5-(4-methylphenyl)-4-phenyl-5-(4-piperazin-1-ylphenyl)pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0270	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-piperazin-1-ylphenyl)pent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0280	uM
3-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-yl-3,6-dihydro-2H-pyridin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0300	uM
4-[(Z)-5-hydroxy-1-[4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0300	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0340	uM
4-[(E)-1-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0440	uM
4-[(E)-5-hydroxy-2-phenyl-1-(4-piperidin-4-ylphenyl)pent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0480	uM
4-[(E)-1-[4-(4-ethylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0500	uM
4-[(Z)-1-[4-[2-(2-azaspiro[4.4]nonan-2-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0500	uM
4-[(E)-1-[4-(4-cyclobutylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0530	uM
4-[(Z)-1-[4-[3-(dimethylamino)propoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0580	uM
4-[(E)-5-hydroxy-1-[4-(4-methylpiperazin-1-yl)phenyl]-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0600	uM
(E)-5-(4-bromophenyl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-4-phenylpent-4-en-1-ol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0600	uM
4-[(E)-1-[4-(azetidin-3-yl)phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0610	uM
Tamoxifen	1464223: Binding affinity to human ERRgamma	ic50	0.0622	uM
(E)-5-(4-bromophenyl)-5-[4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]-4-phenylpent-4-en-1-ol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0640	uM
4-[(Z)-5-hydroxy-2-phenyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0670	uM
4-[(Z)-1-[4-[2-(aziridin-1-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0700	uM
4-[(E)-2-(4-fluorophenyl)-5-hydroxy-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0760	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0770	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol	1704157: Inverse agonist activity at ERRgamma (unknown origin) by luciferase reporter gene assay	ic50	0.0770	uM
4-[(Z)-1-[4-[2-(diethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1317931: Inverse agonist activity at ERRgamma (unknown origin) expressed in human AD293 cells after 24 hrs by beta-galactosidase/luciferase reporter gene assay	ic50	0.0790	uM
4-[(Z)-1-[4-[2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0790	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(1R,2S,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0830	uM
N-[(E)-(4-tert-butylphenyl)methylideneamino]-4-hydroxybenzamide	1374995: Agonist activity at human N-terminal alphaHis-SUMO-tagged ERRgamma-LBD (229 to 458 residues) expressed in Escherichia coli BL21 gold (DE3) cells assessed as decrease in RIP140 peptide recruitment after 2 hrs by TR-FRET assay	ec50	0.0840	uM
4-[(Z)-5-hydroxy-1-[4-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethoxy]phenyl]-2-phenylpent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0910	uM
4-[(Z)-5-hydroxy-2-phenyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]pent-1-enyl]phenol;hydrochloride	1686562: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein PGC1alpha as coactivator incubated for 1 hr by LanthaScreen TR-FRET co-regulator assay	ic50	0.0930	uM
4-[(E)-5-hydroxy-2-phenyl-1-[4-(1-propan-2-ylpiperidin-4-yl)phenyl]pent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0950	uM
4-[(E)-1-[4-(1-cyclopropylpyrrolidin-3-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;hydrochloride	1704113: Binding affinity to ERRgamma (unknown origin) by TR-FRET assay	ic50	0.0960	uM
4-[(E)-1-[4-(4-cyclohexylpiperazin-1-yl)phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0990	uM
4-[(E)-5-hydroxy-2-phenyl-1-(4-piperazin-1-ylphenyl)pent-1-enyl]phenol;dihydrochloride	1614392: Binding affinity to GST-tagged ERRgamma LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.1040	uM

CTD chemical–gene interactions

81 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, increases expression, affects binding, affects expression, decreases activity (+6 more)	25
afimoxifene	affects binding, decreases activity, decreases reaction, affects activity	11
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Diethylstilbestrol	decreases reaction, increases expression, affects activity, affects binding, decreases activity (+1 more)	6
Benzo(a)pyrene	affects methylation, decreases expression	4
Tamoxifen	decreases reaction, affects activity, affects binding, decreases expression	3
Aflatoxin B1	increases methylation, affects expression, decreases methylation	3
daidzein	affects binding, increases reaction, decreases reaction, increases expression	2
trichostatin A	increases activity, increases expression	2
4-isopropylphenol	affects binding, increases activity, decreases activity, decreases reaction	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	2
arachidonyl-2-chloroethylamide	increases expression, affects reaction	2
2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane	affects binding, increases activity, decreases activity, decreases reaction	2
4-cumylphenol	affects binding, increases activity	2
bisphenol S	decreases reaction, increases expression, affects binding	2
Vorinostat	affects cotreatment, increases expression	2
Estradiol	increases expression, affects binding	2
Nickel	decreases expression	2
Genistein	increases expression, affects binding, increases reaction, decreases reaction	2
aristolochic acid I	decreases expression	1
bisphenol F	increases activity	1
biochanin A	increases reaction, affects binding	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propylparaben	affects binding, decreases reaction	1
pirinixic acid	decreases expression, increases activity, affects binding	1
butylphen	increases activity	1
chlorocresol	affects binding, decreases reaction	1
4,4’-bisphenol F	affects binding, decreases reaction	1

ChEMBL screening assays

135 unique, capped per target: 121 binding, 13 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1679777	Functional	Antagonist activity at ERRgamma LBD assessed as inhibition of recruitment of GST-labeled coactivator Scr2 by TR-FRET assay	Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. — J Med Chem
CHEMBL1961859	Binding	Effect on ERR3(NR3B3) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature
CHEMBL4047020	ADMET	Binding affinity to human ERRgamma	Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1L6	SEES3-1V human ESRRG, clone1	Embryonic stem cell	Male
CVCL_A1L7	SEES3-1V human ESRRG, clone2	Embryonic stem cell	Male
CVCL_A1L8	SEES3-1V human ESRRG, clone3	Embryonic stem cell	Male
CVCL_SM45	HAP1 ESRRG (-)	Cancer cell line	Male

Clinical trials (associated diseases)

184 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	PHASE4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT01838278	PHASE3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT00001929	PHASE2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	PHASE2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	PHASE2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	PHASE2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	PHASE2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	PHASE2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT00001663	PHASE1	COMPLETED	Treatment of Cortical Myoclonus With Repetitive Transcranial Magnetic Stimulation
NCT02589340	PHASE1	TERMINATED	Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced Dyskinesia
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT00036296	PHASE1/PHASE2	COMPLETED	Effects of Talampanel on Patients With Advanced Parkinson’s Disease
NCT00037167	PHASE1/PHASE2	COMPLETED	Effects of Exercise Poles on Older Adults During Exercise Walking
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT03775538	PHASE1/PHASE2	COMPLETED	Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease. Extension to HP-CD-CL-2002 Clinical Study
NCT04228653	PHASE1/PHASE2	UNKNOWN	Long-Term Follow-up Safety After DDS Implantation With/Without CDNF Infusions
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT00500994	EARLY_PHASE1	COMPLETED	Neurobiology of Functional Movement Disorder and Non-Epileptic Seizures
NCT00001208	Not specified	RECRUITING	Botulinum Toxin for the Treatment of Involuntary Movement Disorders
NCT00001252	Not specified	RECRUITING	Human Movement Database
NCT00001324	Not specified	COMPLETED	PET Scan to Study Brain Control of Human Movement
NCT00001361	Not specified	COMPLETED	Magnetic Resonance Imaging Studies of Motor and Thought Processes
NCT00001549	Not specified	COMPLETED	Diagnosis and Natural History Study of Patients With Neurological Conditions
NCT00001665	Not specified	COMPLETED	Transcranial Magnetic Stimulation for the Treatment of Parkinson’s Disease
NCT00001667	Not specified	COMPLETED	Genotype/Phenotype Correlation of Movement Disorders and Other Neurological Diseases
NCT00001780	Not specified	COMPLETED	Magnetic Stimulation of the Human Nervous System
NCT00017966	Not specified	COMPLETED	Brain Excitability During Self-Paced Voluntary Movements
NCT00017979	Not specified	COMPLETED	Study of Brain Control of Movement
NCT00018889	Not specified	RECRUITING	Phenotype/Genotype Correlations in Movement Disorders
NCT00042120	Not specified	COMPLETED	Farming and Movement Evaluation Study (FAME)
NCT00056888	Not specified	COMPLETED	Neurophysiological Studies in Patients With Paroxysmal Hyperkinetic Movement Disorders