NR4A2

Summary

NR4A2 (nuclear receptor subfamily 4 group A member 2, HGNC:7981) is a protein-coding gene on chromosome 2q24.1, encoding Nuclear receptor subfamily 4 group A member 2 (P43354). Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 4929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 250 total — 27 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 98
• Druggable target: yes — 14 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 67 downstream targets (CollecTRI)
• MANE Select transcript: NM_006186

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7981
Approved symbol	NR4A2
Name	nuclear receptor subfamily 4 group A member 2
Location	2q24.1
Locus type	gene with protein product
Status	Approved
Aliases	TINUR, NOT, RNR1, HZF-3
Ensembl gene	ENSG00000153234
Ensembl biotype	protein_coding
OMIM	601828
Entrez	4929

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000339562, ENST00000406048, ENST00000409108, ENST00000409572, ENST00000417764, ENST00000417972, ENST00000421709, ENST00000424077, ENST00000426264, ENST00000429376, ENST00000675870, ENST00000700228, ENST00000700229, ENST00000700230, ENST00000700231, ENST00000871392, ENST00000871393, ENST00000871394, ENST00000871395, ENST00000944325

RefSeq mRNA: 2 — MANE Select: NM_006186 NM_006186, NM_173173

CCDS: CCDS2201, CCDS86887

Canonical transcript exons

ENST00000339562 — 8 exons

Exon	Start	End
ENSE00001009594	156324437	156326000
ENSE00001009596	156326718	156326920
ENSE00001009597	156327851	156328014
ENSE00001009598	156326150	156326328
ENSE00001009599	156332480	156332721
ENSE00001009600	156330668	156330791
ENSE00001615082	156328404	156328533
ENSE00003507132	156329323	156330188

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.9675 / max 2937.4983, expressed in 1275 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31347	29.3388	1123
31359	0.6597	322
31344	0.4610	152
31342	0.1468	48
31343	0.1241	61
31346	0.0940	43
31341	0.0838	33
31345	0.0592	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of paranasal sinus	UBERON:0005030	99.20	gold quality
mucosa of stomach	UBERON:0001199	97.37	gold quality
trachea	UBERON:0003126	95.86	gold quality
dorsal root ganglion	UBERON:0000044	95.74	gold quality
cartilage tissue	UBERON:0002418	95.21	gold quality
mucosa of urinary bladder	UBERON:0001259	95.01	gold quality
cardia of stomach	UBERON:0001162	94.99	gold quality
seminal vesicle	UBERON:0000998	94.77	gold quality
trigeminal ganglion	UBERON:0001675	94.76	gold quality
cauda epididymis	UBERON:0004360	94.64	gold quality
bronchial epithelial cell	CL:0002328	93.62	gold quality
tibial nerve	UBERON:0001323	93.41	gold quality
left ovary	UBERON:0002119	93.17	gold quality
gall bladder	UBERON:0002110	92.97	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.82	gold quality
parotid gland	UBERON:0001831	92.46	gold quality
lower lobe of lung	UBERON:0008949	92.35	gold quality
vena cava	UBERON:0004087	92.26	gold quality
bronchus	UBERON:0002185	92.16	gold quality
epithelium of bronchus	UBERON:0002031	92.07	gold quality
sural nerve	UBERON:0015488	91.99	gold quality
cortical plate	UBERON:0005343	91.64	gold quality
pleura	UBERON:0000977	91.37	gold quality
sperm	CL:0000019	91.11	gold quality
parietal pleura	UBERON:0002400	91.09	gold quality
popliteal artery	UBERON:0002250	90.96	gold quality
tibial artery	UBERON:0007610	90.94	gold quality
visceral pleura	UBERON:0002401	90.81	gold quality
pericardium	UBERON:0002407	90.67	gold quality
nasal cavity epithelium	UBERON:0005384	90.28	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-CURD-95	yes	1851.90
E-MTAB-9435	yes	1156.83
E-MTAB-8381	yes	1058.47
E-MTAB-6701	yes	133.39
E-HCAD-1	yes	42.54
E-GEOD-84465	yes	36.62
E-HCAD-4	yes	34.39
E-MTAB-6678	yes	32.28
E-MTAB-10287	yes	31.82
E-CURD-122	yes	27.45
E-GEOD-135922	yes	23.84
E-CURD-46	yes	19.76
E-CURD-88	yes	14.67
E-HCAD-29	no	7103.82
E-CURD-89	no	1894.40

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

67 targets.

Target	Regulation
ADAM2
APOM	Unknown
AXIN2
BAX	Repression
BDNF	Unknown
BGLAP
BTAF1
CCL2	Repression
CCL3	Repression
CD44
CD74
CDKN1C	Activation
CDKN2C	Activation
COL1A1	Unknown
CRH	Unknown
CRHR1
CXCL8	Unknown
CYP11B2	Activation
CYP19A1	Repression
CYP21A1P
CYP21A2	Unknown
DBH
DDC	Unknown
DLK1
DUSP1
EEF1A2
FABP5	Activation
FOXP3	Activation
GCH1	Activation
GFM1

JASPAR motifs

Motif	Name	Family
MA0160.1	NR4A2	NGFI-B-related receptors (NR4)
MA0160.2	NR4A2	NGFI-B-related receptors (NR4)
MA0160.3	NR4A2	NGFI-B-related receptors (NR4)
MA1147.1	NR4A2::RXRA	NGFI-B-related receptors (NR4)::RXR-related receptors (NR2)
MA1147.2	NR4A2::RXRA	NGFI-B-related receptors (NR4)::RXR-related receptors (NR2)

JASPAR matrix evidence (PMIDs): PMID:17916232, PMID:7705655

Upstream regulators (CollecTRI, top): ATF2, C1QTNF1, CREB1, FOXA1, FOXA2, FOXN4, LMX1A, LMX1B, NFKB1, NFKB, NR3C1, NR4A2, POU4F2, RELA, SATB2

miRNA regulators (miRDB)

166 targeting NR4A2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The result suggests that the c.-469delG and possibly other variants of the NR4A2 gene may be of relevance to the complex factors involved in the pathogenesis of schizophrenia. (PMID:11803525)
• may contribute to susceptibility to alcoholism. (PMID:11840500)
• NURR1 induction by proinflammatory mediators represents a point of convergence of at least two distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals. (PMID:11884470)
• A homozygous polymorphism has been found in intron 6 of Nurr1 gene, which was significantly higher in Parkinson’s subjects compared to control. (PMID:11914402)
• Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers (PMID:11959923)
• Mutations in NR4A2 associated with familial Parkinson disease (PMID:12496759)
• Nurr1, NGFI-B and NOR-1 mRNA are expressed constitutively in various human neural and non-neural cell lines, and their levels are up-regulated in human neurons by activation of protein kinase A or protein kinase C pathway. (PMID:12564761)
• Data do not support the notion that the NR4A2 gene plays a major role in risk for schizophrenia among Japanese individuals. (PMID:12627459)
• Nurr1 may play a direct role for specification of DA neurotransmitter identity by activating TH gene transcription in a cell context-dependent manner (PMID:12694388)
• The common heterozygous NI6P is associated with an increased risk of Parkinson disease and an association of borderline significance was found for the homozygous NI6P and diffuse Lewy body disease. (PMID:12756136)
• crystal structure of the orphan receptor Nurr1 at 2.2 A resolution; structure-activity relationship (PMID:12774125)
• NURR1 promoter polymorphisms were studied in Parkinson’s disease (PD), schizophrenia (SZ), and personality traits and found unlikely to be involved in conferring susceptibility for SZ or PD. (PMID:12815740)
• Point mutations in exon 1 are not major cause of familial Parkinson disease (PMID:12827450)
• NURR1 is a nuclear receptor which can assume an active conformation in the absence of a ligand agonist. (PMID:12852843)
• The genes identified here are novel candidates as key early mediators of VEGF-induced endothelial functions. (PMID:14525795)
• Nurr1 activates the OPN promoter directly in osteoblastic cells and may have a role in the regulation of bone homeostasis (PMID:14988426)
• NR4A2 (A NEWLY DISCOVERED MUTANT GENE)IS A MEMBER OF A NUCLEAR RECEPTOR SUPERFAMILY REQUIRED FOR THE DIFFERENTIATION AND MAINTENANCE OF NIGRAL DOPAMINERGIC NEURONS. LOCATION 2Q22-23(P.81) (PMID:15018843)
• To evaluate the role of NR4A2 in PD, exon 1 was analyzed in 108 families with apparent autosomal dominant PD. None of the previously described mutations were found by sequence analysis of the 481 bp fragment of exon 1; no new sequence variants were found. (PMID:15184637)
• Polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with familial Parkinson disease. (PMID:15197702)
• search for all known mutations in 176 Caucasian Portuguese and 82 Caucasian Brazilian subjects with lifetime diagnosis of schizophrenia failed to identify any of the described mutations in patients or controls (PMID:15211629)
• Expression of Nurr1 and NGFI-B plays an important role in human adrenal cortex and its neoplasms, including possible regulation of steroidogenesis. (PMID:15292355)
• Virtually all striatal cells that stain for tyrosine hydroxylase also express Nurr1, confirming the existence of dopaminergic neurons intrinsic to the human striatum. (PMID:15450088)
• Causal relationship between the rapid decline of aromatase mRNA and induction of orphan nuclear receptors NURR1 and NGFI-B expression, which concomitantly occur upon LH surge at the later stages of ovarian follicular development. (PMID:15486232)
• down-regulation of NR4A2 as well as NR4A1 promoted intrinsic apoptosis (PMID:15548686)
• NR4A nuclear receptors NR4A1, NR4A2, NR4A3 are potential transcriptional mediators of inflammatory signals in activated macrophages (PMID:15964844)
• NR4A2 can stimulate progression of colorectal cancer downstream from cyclooxygenase 2-derived PGE2. (PMID:16293616)
• In Parkinsons, Nurr1 was decreased in nigral neurons containing alpha-synuclein-immunoreactive inclusions. In Alzheimer’s, Nurr1 was decreased in neurons containing neurofibrillary tangles. In PSP, Nurr1 was also decreased. (PMID:16320253)
• Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain dopamine neuron phenotype in murine and human ES cell cultures. (PMID:16477036)
• Nur77, Nurr1, and NOR-1 are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of these factors in atherogenesis. (PMID:16873729)
• Insights into the mechanisms of transcription via the Nurr1 LBD identifies an alternative co-activator-binding surface that is unique to the NR4A family of NRs. (PMID:17032747)
• Nurr1 has a protective function in cartilage homeostasis by selectively repressing matrix metalloproteinase gene expression during inflammation. (PMID:17283078)
• This study examines whether BDNF V66M (c.196 G –> A) or NR4A2 IVS6 +18insG polymorphism is associated with the risk of Taiwanese Parkinson’s disease and the age of onset using a case-control study. (PMID:17427185)
• These results suggest that the suppression of aromatase activity and its transcription level by MEHP exposure to NCI-H295R cells was regulated through the rapid and transient expression of Nur77 gene. (PMID:17574328)
• aberrant expression and distribution of NURR1 in psoriasis (PMID:17671512)
• Nurr1 phosphorylation by ERK2 may play a role in regulating the TH expression. (PMID:17681692)
• Significant alteration of mRNA expression of Nurr1, a transcription factor that regulates dopamine transporter expression, is confined to the paranigral nucleus. (PMID:18057194)
• Rat and mouse species-dependent differences of Nurr1 and Ngn2 actions in dopamine neuron differentiation. (PMID:18242186)
• These data identify the NR4A receptor family as potential mediators of an MC1R-coordinated DNA damage response to ultraviolet rays exposure in melanocytic cells. (PMID:18292087)
• decreased expression of Nurr1, which has been found in Parkinson’s disease patients with Nurr1 mutations, was shown to transcriptionally increase alpha-synuclein expression (PMID:18463503)
• The induction of nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy is reported. (PMID:18577687)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr4a2a	ENSDARG00000017007
mus_musculus	Nr4a2	ENSMUSG00000026826
rattus_norvegicus	Nr4a2	ENSRNOG00000005600
drosophila_melanogaster	Hr38	FBGN0014859
caenorhabditis_elegans		WBGENE00003605

Paralogs (2): NR4A3 (ENSG00000119508), NR4A1 (ENSG00000123358)

Protein

Protein identifiers

Nuclear receptor subfamily 4 group A member 2 — P43354 (reviewed: P43354)

Alternative names: Immediate-early response protein NOT, Orphan nuclear receptor NURR1, Transcriptionally-inducible nuclear receptor

All UniProt accessions (11): P43354, A0A8V8TPF8, A0A8V8TPV9, A0A8V8TR19, C9IYM5, C9J8W4, C9JWQ1, E9PBQ4, F1D8N6, F1DAL2, F8W6I3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons.

Subunit / interactions. Interacts with SFPQ, NCOR2, SIN3A and HADC1. The interaction with NCOR2 increases in the absence of PITX3. Interacts with PER2.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in a number of cell lines of T-cell, B-cell and fibroblast origin. Strong expression in brain tissue.

Disease relevance. Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism (IDLDP) [MIM:619911] An autosomal dominant disorder characterized by global developmental delay affecting motor, cognitive, and speech domains apparent in early childhood or infancy. Most patients also show movement abnormalities, often hypotonia with later development of dopa-responsive dystonia or parkinsonism. About half of patients develop various types of seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ligand-binding domain (LBD) contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. NR4A2 lacks a ‘classical’ binding site for coactivators.

Similarity. Belongs to the nuclear hormone receptor family. NR4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P43354-1	1	yes
P43354-2	2

RefSeq proteins (2): NP_006177, NP_775265 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR003070	NR4A1-3	Family
IPR003073	NR4A2	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily

Pfam: PF00104, PF00105

UniProt features (48 total): helix 17, sequence variant 7, short sequence motif 4, turn 4, strand 4, compositionally biased region 2, sequence conflict 2, zinc finger region 2, region of interest 2, chain 1, domain 1, splice variant 1, DNA-binding region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5Y41	X-RAY DIFFRACTION	2.05
1OVL	X-RAY DIFFRACTION	2.2
5YD6	X-RAY DIFFRACTION	2.34
8CYO	X-RAY DIFFRACTION	2.41
6L6Q	X-RAY DIFFRACTION	2.6
6L6L	X-RAY DIFFRACTION	2.78
7WNH	X-RAY DIFFRACTION	3.1
6DDA	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43354-F1	66.39	0.42

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors

MSigDB gene sets: 777 (showing top): TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, LEE_SP4_THYMOCYTE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_AMINE, GAANYNYGACNY_UNKNOWN, ENK_UV_RESPONSE_KERATINOCYTE_UP, AMIT_EGF_RESPONSE_60_HELA, GCANCTGNY_MYOD_Q6, GOBP_NEURON_MATURATION

GO Biological Process (34): negative regulation of transcription by RNA polymerase II (GO:0000122), response to hypoxia (GO:0001666), neuron migration (GO:0001764), response to amphetamine (GO:0001975), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), adult locomotory behavior (GO:0008344), post-embryonic development (GO:0009791), central nervous system projection neuron axonogenesis (GO:0021952), central nervous system neuron differentiation (GO:0021953), habenula development (GO:0021986), cellular response to oxidative stress (GO:0034599), regulation of dopamine metabolic process (GO:0042053), dopamine biosynthetic process (GO:0042416), neuron maturation (GO:0042551), negative regulation of neuron apoptotic process (GO:0043524), regulation of respiratory gaseous exchange (GO:0043576), fat cell differentiation (GO:0045444), positive regulation of transcription by RNA polymerase II (GO:0045944), neuron apoptotic process (GO:0051402), general adaptation syndrome (GO:0051866), canonical Wnt signaling pathway (GO:0060070), cellular response to corticotropin-releasing hormone stimulus (GO:0071376), dopaminergic neuron differentiation (GO:0071542), midbrain dopaminergic neuron differentiation (GO:1904948), negative regulation of apoptotic signaling pathway (GO:2001234), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), gene expression (GO:0010467), regulation of gene expression (GO:0010468), intracellular receptor signaling pathway (GO:0030522), dopamine metabolic process (GO:0042417), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (16): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), nuclear receptor activity (GO:0004879), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), nuclear glucocorticoid receptor binding (GO:0035259), nuclear retinoid X receptor binding (GO:0046965), protein heterodimerization activity (GO:0046982), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), nuclear speck (GO:0016607), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
dopamine metabolic process	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
response to stress	1
response to decreased oxygen levels	1
cell migration	1
generation of neurons	1
response to amine	1
gene expression	1
RNA biosynthetic process	1
DNA-templated transcription	1
locomotory behavior	1
adult behavior	1
multicellular organism development	1
multicellular organismal process	1
central nervous system neuron axonogenesis	1
central nervous system development	1
neuron differentiation	1
epithalamus development	1
anatomical structure development	1
response to oxidative stress	1
cellular response to chemical stress	1
regulation of catecholamine metabolic process	1
catecholamine biosynthetic process	1
cell maturation	1
neuron development	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
respiratory gaseous exchange by respiratory system	1
regulation of multicellular organismal process	1
cell differentiation	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR4A2	PITX3	O75364	965
NR4A2	PER2	O15055	935
NR4A2	LMX1A	Q8TE12	849
NR4A2	TH	P07101	837
NR4A2	SLC18A2	Q05940	802
NR4A2	SLC6A3	Q01959	788
NR4A2	SNCA	P37840	748
NR4A2	EGR1	P18146	723
NR4A2	RCOR1	Q9UKL0	721
NR4A2	LMX1B	O60663	718
NR4A2	EN1	Q05925	697
NR4A2	FOSB	P53539	693
NR4A2	DDC	P20711	675
NR4A2	TCF12	Q99081	673
NR4A2	FOXA2	Q9Y261	671

IntAct

32 interactions, top by confidence:

A	B	Type	Score
NR4A2	CDKN2D	psi-mi:“MI:0915”(physical association)	0.670
NR4A2	ODAD2	psi-mi:“MI:0915”(physical association)	0.560
APP	NR4A2	psi-mi:“MI:0915”(physical association)	0.560
NR4A2	TCEAL5	psi-mi:“MI:0915”(physical association)	0.520
FDX1	NR4A2	psi-mi:“MI:0915”(physical association)	0.400
	NR4A2	psi-mi:“MI:0915”(physical association)	0.370
IFNA5	NR4A2	psi-mi:“MI:0915”(physical association)	0.370
IL20	NR4A2	psi-mi:“MI:0915”(physical association)	0.370
NR4A2	RXRB	psi-mi:“MI:0915”(physical association)	0.370
CDKN2D	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
ODAD2	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
NR4A2	GTF2I	psi-mi:“MI:0915”(physical association)	0.000
CISD1	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
TCEAL5	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
NR4A2	RAN	psi-mi:“MI:0915”(physical association)	0.000
ZCCHC17	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
NR4A2	OPA1	psi-mi:“MI:0915”(physical association)	0.000
ZNF41	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
NR4A2	ANP32E	psi-mi:“MI:0915”(physical association)	0.000
BAZ1B	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
NR4A2	NEFM	psi-mi:“MI:0915”(physical association)	0.000
NDUFS5	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
EIF3A	NR4A2	psi-mi:“MI:0915”(physical association)	0.000
SUGP2	NR4A2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): NR4A2 (Two-hybrid), NR4A2 (Protein-peptide), RXRA (Two-hybrid), RXRA (Reconstituted Complex), NR4A2 (Affinity Capture-Western), NR4A2 (Affinity Capture-Western), NR4A2 (Two-hybrid), ARMC4 (Two-hybrid), NR4A2 (Biochemical Activity), Mapk1 (Affinity Capture-Western), Mapk1 (Reconstituted Complex), MAPK1 (Affinity Capture-Western), MAPK3 (Affinity Capture-Western), NR4A2 (Affinity Capture-MS), NR4A2 (Two-hybrid)

ESM2 similar proteins: A0A1L8GWK2, A0A571BF63, A0JMA8, A0JNE3, A2BGA0, A4IIG7, O00443, P13056, P24781, P28701, P28705, P43354, P45448, P48443, P51128, P51129, Q04913, Q06219, Q07917, Q08E53, Q09555, Q0GFF6, Q0IHW3, Q0VC20, Q1LVF3, Q26622, Q33E94, Q505F1, Q5BJR8, Q5FWP2, Q5R5Y4, Q5RAY1, Q5RCZ5, Q5REL6, Q5RJH6, Q61194, Q64287, Q68F67, Q6DHP9, Q7TNK1

Diamond homologs: A0JNE3, A2T928, A4IIG7, G5ECR9, G5EDJ0, O02151, O45666, O76202, O97716, P10276, P10588, P10826, P10827, P10828, P11416, P12813, P13056, P13631, P16376, P18117, P18514, P18515, P18516, P18911, P20153, P22448, P22449, P22605, P22736, P22829, P28699, P31396, P33242, P33244, P41828, P41830, P43354, P45447, P49116, P49117

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
NR3C1	“down-regulates quantity by repression”	NR4A2	“transcriptional regulation”
MAPK1	up-regulates	NR4A2	phosphorylation
SATB2	“down-regulates quantity”	NR4A2	“transcriptional regulation”
MAPK7	“up-regulates activity”	NR4A2	phosphorylation
RXRB	up-regulates	NR4A2	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	25
Uncertain significance	151
Likely benign	28
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1339340	GRCh37/hg19 2q24.1(chr2:157058119-157183736)x1	Pathogenic
1685988	NM_006186.4(NR4A2):c.896G>T (p.Cys299Phe)	Pathogenic
1693495	NM_006186.4(NR4A2):c.839G>A (p.Cys280Tyr)	Pathogenic
1693496	NM_006186.4(NR4A2):c.914G>A (p.Cys305Tyr)	Pathogenic
1693498	NM_006186.4(NR4A2):c.956G>A (p.Arg319Gln)	Pathogenic
1710386	NM_006186.4(NR4A2):c.698del (p.Pro233fs)	Pathogenic
2576541	NM_006186.4(NR4A2):c.591_592del (p.Leu198fs)	Pathogenic
3338013	NM_006186.4(NR4A2):c.44_45insA (p.Ser16fs)	Pathogenic
3338016	NM_006186.4(NR4A2):c.534del (p.Phe178fs)	Pathogenic
3338024	NM_006186.4(NR4A2):c.1159-81_1540+67del	Pathogenic
3338025	NM_006186.4(NR4A2):c.1del (p.Met1fs)	Pathogenic
3338030	NM_006186.4(NR4A2):c.536del (p.Lys179fs)	Pathogenic
3338047	NM_006186.4(NR4A2):c.-2-2del	Pathogenic
3338476	NM_006186.4(NR4A2):c.14_15insT (p.Gln5fs)	Pathogenic
3338477	NM_006186.4(NR4A2):c.548del (p.Pro183fs)	Pathogenic
3338478	NM_006186.4(NR4A2):c.30_31insG (p.Ser11fs)	Pathogenic
3342357	NM_006186.4(NR4A2):c.174dup (p.Ser59fs)	Pathogenic
3773737	NM_006186.4(NR4A2):c.706C>T (p.Gln236Ter)	Pathogenic
3893207	NM_006186.4(NR4A2):c.995-1G>A	Pathogenic
3912065	NM_006186.4(NR4A2):c.460C>T (p.Gln154Ter)	Pathogenic
4082007	NM_006186.4(NR4A2):c.603del (p.Pro201_Met202insTer)	Pathogenic
4291747	NM_006186.4(NR4A2):c.377C>A (p.Ser126Ter)	Pathogenic
4537603	NM_006186.4(NR4A2):c.286del (p.Gln96fs)	Pathogenic
4755530	NM_006186.4(NR4A2):c.80C>A (p.Ser27Ter)	Pathogenic
4840571	NM_006186.4(NR4A2):c.895T>A (p.Cys299Ser)	Pathogenic
946314	NM_006186.4(NR4A2):c.968G>T (p.Cys323Phe)	Pathogenic
985332	NM_006186.4(NR4A2):c.325dup (p.Gln109fs)	Pathogenic
1321298	NM_006186.4(NR4A2):c.1157_1158insCCTGGACTAGACCAGCCTGGACTATTCCAG (p.Arg386delinsSerLeuAspTer)	Likely pathogenic
1700112	NM_006186.4(NR4A2):c.943T>C (p.Cys315Arg)	Likely pathogenic
1992352	NM_006186.4(NR4A2):c.854G>A (p.Gly285Asp)	Likely pathogenic

SpliceAI

1107 predictions. Top by Δscore:

Variant	Effect	Δscore
2:156325997:CTCT:C	acceptor_gain	1.0000
2:156325998:TCT:T	acceptor_gain	1.0000
2:156325998:TCTC:T	acceptor_loss	1.0000
2:156325999:CT:C	acceptor_gain	1.0000
2:156325999:CTC:C	acceptor_gain	1.0000
2:156326000:TCTGC:T	acceptor_gain	1.0000
2:156326001:C:CC	acceptor_gain	1.0000
2:156326011:CA:C	acceptor_gain	1.0000
2:156326012:A:C	acceptor_gain	1.0000
2:156326012:A:T	acceptor_gain	1.0000
2:156326017:C:CT	acceptor_gain	1.0000
2:156326018:A:T	acceptor_gain	1.0000
2:156327849:AC:A	donor_gain	1.0000
2:156327850:CC:C	donor_gain	1.0000
2:156328010:AACCA:A	acceptor_gain	1.0000
2:156328011:ACCA:A	acceptor_gain	1.0000
2:156328012:CCA:C	acceptor_gain	1.0000
2:156328012:CCAC:C	acceptor_gain	1.0000
2:156328013:CA:C	acceptor_gain	1.0000
2:156328013:CAC:C	acceptor_gain	1.0000
2:156328015:C:CC	acceptor_gain	1.0000
2:156328400:CTACC:C	donor_loss	1.0000
2:156328401:TACC:T	donor_loss	1.0000
2:156328402:ACC:A	donor_loss	1.0000
2:156328403:C:CG	donor_loss	1.0000
2:156328530:TGCG:T	acceptor_gain	1.0000
2:156328532:CG:C	acceptor_gain	1.0000
2:156328534:C:CC	acceptor_gain	1.0000
2:156332476:TCACT:T	donor_loss	1.0000
2:156332477:CA:C	donor_loss	1.0000

AlphaMissense

3961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:156325814:A:G	L576P	1.000
2:156325819:G:C	F574L	1.000
2:156325819:G:T	F574L	1.000
2:156325821:A:G	F574L	1.000
2:156325826:C:G	R572P	1.000
2:156325832:A:G	L570P	1.000
2:156325835:C:T	G569E	1.000
2:156325836:C:A	G569W	1.000
2:156325836:C:G	G569R	1.000
2:156325836:C:T	G569R	1.000
2:156325856:A:G	L562P	1.000
2:156325856:A:T	L562H	1.000
2:156325937:A:G	L535P	1.000
2:156326244:C:A	W482C	1.000
2:156326244:C:G	W482C	1.000
2:156326246:A:G	W482R	1.000
2:156326246:A:T	W482R	1.000
2:156326284:A:T	V469D	1.000
2:156326291:C:A	G467W	1.000
2:156326718:C:A	R454M	1.000
2:156326733:A:G	L449P	1.000
2:156326766:A:G	L438P	1.000
2:156326821:A:G	W420R	1.000
2:156326821:A:T	W420R	1.000
2:156326850:A:G	L410P	1.000
2:156326853:A:G	L409P	1.000
2:156327906:A:G	L368P	1.000
2:156327975:A:C	L345W	1.000
2:156327975:A:G	L345S	1.000
2:156327979:G:T	R344S	1.000

dbSNP variants (sampled 300 via entrez): RS1000169144 (2:156331529 T>A), RS1000286391 (2:156331097 G>A), RS1000545817 (2:156323960 T>C), RS1000623873 (2:156332288 C>T), RS1000797409 (2:156324084 A>C), RS1000935109 (2:156332094 T>G), RS1001292862 (2:156331827 G>C), RS1001859485 (2:156324620 C>T), RS1001865534 (2:156331383 T>C), RS1001963926 (2:156324401 T>C), RS1001993697 (2:156325090 CTT>C,CT,CTTT,CTTTT), RS1002300450 (2:156330251 C>A,G,T), RS1002414982 (2:156330560 C>T), RS1003135527 (2:156332657 G>A), RS1003232617 (2:156326487 A>G)

Disease associations

OMIM: gene MIM:601828 | disease phenotypes: MIM:619911, MIM:168600, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (7): intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism (MONDO:0859257), complex neurodevelopmental disorder (MONDO:0100038), late-onset Parkinson disease (MONDO:0008199), autism (MONDO:0005260), autism spectrum disorder (MONDO:0005258), epilepsy (MONDO:0005027), neurodevelopmental disorder (MONDO:0700092)

Orphanet (4): Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome (Orphanet:660017), Non-specific syndromic intellectual disability (Orphanet:528084), Hereditary late-onset Parkinson disease (Orphanet:411602), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

98 total (30 of 98 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000175	Cleft palate
HP:0000190	Abnormal oral frenulum morphology
HP:0000274	Small face
HP:0000298	Mask-like facies
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000525	Abnormality iris morphology
HP:0000568	Microphthalmia
HP:0000589	Coloboma
HP:0000666	Horizontal nystagmus
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000722	Compulsive behaviors
HP:0000726	Dementia
HP:0000729	Autistic behavior
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0001188	Hand clenching

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000635_3	Response to statin therapy	9.000000e-06
GCST000880_24	Menarche (age at onset)	1.000000e-09
GCST002541_41	Menarche (age at onset)	2.000000e-10
GCST002541_42	Menarche (age at onset)	3.000000e-09
GCST003994_2	Age at voice drop	2.000000e-08
GCST005839_7	Depression	2.000000e-08
GCST006482_29	Lung function (FEV1/FVC)	3.000000e-08
GCST006482_30	Lung function (FEV1/FVC)	1.000000e-06
GCST006857_2	Leisure-time exercise behaviour	8.000000e-06
GCST006858_2	Leisure-time exercise behaviour (age-stratified)	2.000000e-07
GCST007692_92	Chronic obstructive pulmonary disease	2.000000e-08
GCST009600_17	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-08
GCST009996_2	HDL cholesterol levels	9.000000e-07
GCST011769_11	Schizophrenia	6.000000e-09
GCST012111_1	Worry too long after an embarrassing experience	3.000000e-07
GCST012114_3	Sociability score	4.000000e-08
GCST012354_7	Anxiety	6.000000e-18

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007888	age at voice drop
EFO:0004713	FEV/FVC ratio
EFO:0000483	exercise
EFO:0007805	HDL cholesterol change measurement
EFO:0009589	worry measurement
EFO:0009592	social interaction measurement
EFO:0009863	anxiety measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885613 (PROTEIN COMPLEX), CHEMBL5002 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

14 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,480,522 (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
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL509	MECLOFENAMIC ACID	4	45,809
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1071	OXAPROZIN	4	51,044
CHEMBL1201753	PITAVASTATIN	4	24,149
CHEMBL1206690	PARECOXIB	4	22,031
CHEMBL2220442	FLUVASTATIN	4	53,699
CHEMBL495	ALPROSTADIL	4	13,450
CHEMBL682	AMODIAQUINE	4	7,153
CHEMBL76	CHLOROQUINE	4	58,679
CHEMBL197194	VIDOFLUDIMUS	3	808
CHEMBL267476	LINOLEIC ACID	2	323,195
CHEMBL61301	TECASTEMIZOLE	2	2,553
CHEMBL8659	OLEIC ACID	2	713,838

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 4A. Nerve growth factor IB-like receptors

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
compound 111 [PMID: 37918435]	Agonist	7.05	pEC50
compound 29 [Vietor, et al., 2023]	Activation	6.96	pEC50
vidofludimus	Activation	6.4	pEC50
compound 108 [PMID: 37918435]	Agonist	5.15	pEC50

ChEMBL bioactivities

194 potent at pChembl≥5 of 311 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.10	EC50	0.8	nM	CHEMBL399603
9.10	EC50	0.7943	nM	CHEMBL5266566
8.46	EC50	3.5	nM	CHEMBL399807
8.41	EC50	3.9	nM	CHEMBL401032
8.39	EC50	4.1	nM	CHEMBL399602
8.30	EC50	5.012	nM	BEXAROTENE
8.00	EC50	10	nM	BEXAROTENE
8.00	EC50	10	nM	CHEMBL5405485
7.92	EC50	12	nM	CHEMBL5405485
7.90	EC50	12.59	nM	CHEMBL3780763
7.90	EC50	12.59	nM	CHEMBL3781132
7.89	EC50	13	nM	CHEMBL5405485
7.85	EC50	14	nM	CHEMBL4473232
7.85	EC50	14	nM	CHEMBL6175985
7.68	EC50	21	nM	CHEMBL5427562
7.66	EC50	22	nM	CHEMBL5427562
7.62	EC50	24	nM	CHEMBL5086921
7.60	EC50	25	nM	CHEMBL4579076
7.58	EC50	26	nM	CHEMBL247879
7.57	EC50	27	nM	CHEMBL6175985
7.50	EC50	31.9	nM	CHEMBL393713
7.42	EC50	38	nM	CHEMBL4475176
7.40	EC50	40	nM	CHEMBL5419377
7.40	EC50	40	nM	CHEMBL6169248
7.37	EC50	43	nM	CHEMBL5427562
7.35	EC50	45	nM	CHEMBL4576867
7.30	EC50	50	nM	CHEMBL5399104
7.23	EC50	59.2	nM	CHEMBL246654
7.22	EC50	60	nM	CHEMBL6171448
7.22	EC50	60	nM	CHEMBL6175985
7.16	EC50	70	nM	CHEMBL5419377
7.16	EC50	70	nM	CHEMBL6175864
7.16	EC50	70	nM	CHEMBL6175985
7.12	EC50	75	nM	CHEMBL4461137
7.11	EC50	77.5	nM	ISOXAZOLOPYRIDINONE
7.10	EC50	79	nM	CHEMBL5405308
7.10	EC50	80	nM	CHEMBL6174136
7.10	Kd	80	nM	CHEMBL6175864
7.06	EC50	87	nM	CHEMBL4455501
7.05	EC50	90	nM	CHEMBL5427562
7.00	EC50	99	nM	CHEMBL4461137
7.00	EC50	100	nM	CHEMBL5395588
7.00	EC50	100	nM	CHEMBL6176601
7.00	EC50	100	nM	CHEMBL6177659
7.00	EC50	100	nM	CHEMBL6162065
6.96	EC50	110	nM	CHEMBL5417085
6.96	EC50	110	nM	CHEMBL5428767
6.96	EC50	110	nM	CHEMBL6175985
6.95	EC50	113.1	nM	CHEMBL247478
6.92	EC50	120	nM	PITAVASTATIN

PubChem BioAssay actives

140 with measured affinity, of 869 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
(E)-3-[4-hydroxy-3-(3-propan-2-ylphenyl)phenyl]prop-2-enoic acid	1925168: Inhibition of Nurr1-RXRalpha (unknown origin) by BRET assay	ec50	0.0008	uM
6-(1,3-benzodioxol-5-yl)-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0008	uM
(2E,4E)-3-methyl-5-[(2S)-2-methyl-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)cyclopropyl]penta-2,4-dienoic acid	1925171: Inhibition of human full length Nurr1-RXRalpha transfected in COS7 cells	ec50	0.0010	uM
6-[4-(2-hydroxyethoxymethyl)phenyl]-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0035	uM
6-[4-(2-methoxyethoxymethyl)phenyl]-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0039	uM
6-(4-methoxyphenyl)-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0041	uM
Bexarotene	1925172: Inhibition of Nurr1-RXRalpha in HEK293T cells by BRET assay	ec50	0.0050	uM
3-[(4-tert-butylphenyl)methoxy]benzoic acid	2037894: Agonist activity at full length human Nurr1 transiently transfected in HEK293T cells co-transfected with pFR-Luc-NurRE incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.0100	uM
4-[(11S,15R)-4,4,7,7-tetramethyl-16-oxatetracyclo[8.6.0.03,8.011,15]hexadeca-1(10),2,8-trien-11-yl]benzoic acid	1286833: Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha/Nurr1 (unknown origin) expressed in HEK293T cells by BRET2 assay	ec50	0.0126	uM
4-[(4aR,11bS)-7,7,10,10-tetramethyl-2,3,4,4a,8,9-hexahydro-1H-naphtho[2,3-b][1]benzofuran-11b-yl]benzoic acid	1286833: Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha/Nurr1 (unknown origin) expressed in HEK293T cells by BRET2 assay	ec50	0.0126	uM
[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-2-fluorophenyl]methanol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0140	uM
3-[(2,4-dichlorophenyl)methoxy]benzoic acid	2037895: Agonist activity at full length human Nurr1 transiently transfected in HEK293T cells co-transfected with pFR-Luc-DR5 incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.0210	uM
2-(4-fluorophenyl)-3H-benzimidazole-5-carboxylic acid	1808435: Agonist activity at full length NURR1 (unknown origin) expressed in mouse MND9 cells by luciferase reporter gene assay	ec50	0.0240	uM
N-(6-fluoro-2-pyridinyl)-6-pyridin-2-ylimidazo[1,2-a]pyridine-2-carboxamide	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0250	uM
6-[4-[(dimethylamino)methyl]phenyl]-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0260	uM
5-methyl-6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0319	uM
[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-2,6-difluorophenyl]methanol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0380	uM
5-(4-phenylmethoxyphenyl)thiophene-2-carboxylic acid	1990710: Agonist activity at full length human Nurr1 transfected in HEK293T cells co-transfected with pFR-Luc-NRBE assessed as luciferase activity incubated for 16 hrs by dual-glo luciferase assay	ec50	0.0400	uM
[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0450	uM
4-[(2-chlorophenyl)methoxy]benzoic acid	2037848: Agonist activity at human Nurr1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.0500	uM
6-(2,4-dimethoxyphenyl)-5-methyl-3-phenyl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0592	uM
1-[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]ethanol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0750	uM
3,6-diphenyl-5H-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.0775	uM
2-[[2-fluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.0790	uM
3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-N-methylbenzamide	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.0870	uM
2-[[4-[3-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.1000	uM
2-[[2-fluoro-4-(3-prop-2-ynoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.1100	uM
3-[(4-chlorophenyl)methoxy]benzoic acid	2037848: Agonist activity at human Nurr1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.1100	uM
5-methyl-3-phenyl-6-[4-(2-propan-2-yloxyethoxymethyl)phenyl]-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.1131	uM
Pitavastatin	1885210: Agonist activity at human Nurr1 measured by Gal4-Nurr1 hybrid reporter gene assay	ec50	0.1200	uM
5-methyl-3-phenyl-6-pyridin-4-yl-[1,2]oxazolo[4,5-c]pyridin-4-one	305001: Activation of Nurr1 expressed in MN9D cells by luciferase reporter gene assay	ec50	0.1299	uM
2-[[2-fluoro-4-(3-propan-2-yloxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.1300	uM
N-phenyl-6-pyridin-2-ylimidazo[1,2-a]pyridine-2-carboxamide	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.1400	uM
2-[[2,6-difluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.2000	uM
2-[[4-(3-butoxyphenyl)-2-fluorophenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.2100	uM
2-[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.2180	uM
2-(4,5-diphenyl-1,3-oxazol-2-yl)acetic acid	2087282: Binding affinity to human N-terminal His6 tagged Nurr1 LBD (362 to 598 residues) expressed in Escherichia coli BL21 (DE3)-R3-pRARE2 assessed as dissociation constant by ITC analysis	kd	0.3000	uM
2-[[2,6-difluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]-4,4-difluorocyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.3000	uM
2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid	1990710: Agonist activity at full length human Nurr1 transfected in HEK293T cells co-transfected with pFR-Luc-NRBE assessed as luciferase activity incubated for 16 hrs by dual-glo luciferase assay	ec50	0.3000	uM
3-[3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]oxetan-3-ol	1572852: Agonist activity at full-length Gal4-fused NOT (unknown origin) expressed in CHO cells by luciferase reporter gene assay	ec50	0.3230	uM
2-[[2,6-difluoro-4-[2-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.3300	uM
2-[[2-fluoro-4-[3-(2-methylpropoxy)phenyl]phenyl]carbamoyl]cyclopentene-1-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.4000	uM
4-[[2,6-difluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]carbamoyl]-2,5-dihydrothiophene-3-carboxylic acid	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.4300	uM
2-N-[2,6-difluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]-1-N-hydroxycyclopentene-1,2-dicarboxamide	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.4600	uM
5-chloro-N-[5-chloro-2-[2-(dimethylamino)ethoxy]phenyl]-1H-indole-6-carboxamide	2015932: Binding affinity to Nurr1 LBD (unknown origin) assessed as dissociation constant by Isothermal titration calorimetry	kd	0.5000	uM
4-[(4-tert-butylphenyl)methoxy]benzoic acid	2037848: Agonist activity at human Nurr1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.5000	uM
4-[(11R,15S)-4,4,7,7-tetramethyl-16-oxatetracyclo[8.6.0.03,8.011,15]hexadeca-1(10),2,8-trien-11-yl]benzoic acid	1286833: Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha/Nurr1 (unknown origin) expressed in HEK293T cells by BRET2 assay	ec50	0.5012	uM
1-N-[2,6-difluoro-4-[3-(trideuteriomethoxy)phenyl]phenyl]cyclopentene-1,2-dicarboxamide	2031365: Agonist activity at human Nurr1-LBD transfected in HEK293T cells co-transfected with pFR-Luc/pRL-SV40 assessed as transfection efficiency by measuring luciferase activity measured after 16 hrs by Gal4 hybrid reporter gene assay	ec50	0.5100	uM
3-[(3-phenylphenyl)methoxy]benzoic acid	2037848: Agonist activity at human Nurr1 LBD transiently transfected in HEK293T cells incubated for 16 hrs by Gal4-hybrid reporter gene based Dual-glo luciferase assay	ec50	0.5200	uM
(E)-3-(4,5-diphenyl-1,3-oxazol-2-yl)prop-2-enoic acid	2087282: Binding affinity to human N-terminal His6 tagged Nurr1 LBD (362 to 598 residues) expressed in Escherichia coli BL21 (DE3)-R3-pRARE2 assessed as dissociation constant by ITC analysis	kd	0.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, affects cotreatment	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
torcetrapib	increases expression	3
Colforsin	decreases reaction, increases expression	3
Tretinoin	affects cotreatment, increases expression, decreases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
methylmercuric chloride	affects reaction, increases expression	2
bisphenol A	decreases expression, increases methylation	2
mono-(2-ethylhexyl)phthalate	increases methylation, increases expression, increases abundance	2
quinocetone	decreases expression, decreases reaction	2
(+)-JQ1 compound	decreases expression, increases expression	2
bisphenol AF	decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, increases methylation	2
Arsenic	decreases expression, affects cotreatment, increases abundance	2
Dichlorodiphenyl Dichloroethylene	decreases expression, increases activity	2
Estradiol	increases expression, decreases expression	2
Formaldehyde	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression, decreases expression	2
Zinc	affects cotreatment, increases expression, affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Thapsigargin	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
SA00025	affects binding, increases activity	1
666-15 compound	decreases reaction, increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1

ChEMBL screening assays

274 unique, capped per target: 273 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3784069	Binding	Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha/Nurr1 (unknown origin) expressed in HEK293T cells by BRET2 assay	Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. — J Med Chem
CHEMBL1227067	Functional	Agonist activity at nuclear orphan receptor Nurr1 expressed in human BGC823 cells co-transfected with fused GAL4-Nurr1(LBD) assessed as transactivation after 12 hrs by transactivation assay	Cytosporone B is an agonist for nuclear orphan receptor Nur77. — Nat Chem Biol

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4W9	SEES3-1V human NR4A2, clone1	Embryonic stem cell	Male
CVCL_A4X0	SEES3-1V human NR4A2, clone2	Embryonic stem cell	Male
CVCL_A4X1	SEES3-1V human NR4A3, clone1	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction