Tchem RORA Nuclear receptor ROR-alpha

Protein Classes

DTO Classes

Protein / Nuclear Receptor / Retinoic Acid-related Orphans / Nuclear Receptor Ror-alpha

Protein Summary

Description

Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development (PubMed:29656859). Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling. The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]

Uniprot Accession IDs

• P35398
• P35397
• P35399
• P45445
• Q495X4
• Q96H83

Gene Name

• RORA

Ensembl ID

• ENST00000261523
• ENSP00000261523
• ENSG00000069667
• ENST00000335670
• ENSP00000335087

Symbol

• NR1F1
• RZRA
• ROR1
• ROR2
• ROR3
• RZRA
• NR1F1
• IDDECA
• RZR-ALPHA

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
kinase perturbation	1
trait	1
transcription factor perturbation	1
biological process	0.99
molecular function	0.99

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Target Illumination GWAS Analytics (TIGA)

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GENEVA

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 243.83   (req: < 5)

Gene RIFs: 95   (req: <= 3)

Antibodies: 523   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 243.83   (req: >= 5)

Gene RIFs: 95   (req: > 3)

Antibodies: 523   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 47

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 7

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

Active Ligands (7)

Explore Active Ligands

1 – 7 of 7

7alpha-hydroxycholesterol

RORATchem NR

Ki : 7.92

7beta-hydroxycholesterol

RORATchem NR

Ki : 7.92

CD2314

RORATchem NR

Kd : 5.42000008

SR1001

RORATchem NR

Ki : 6.76000023

CHEMBL3314003

RORATchem NR

EC50 : 7.54

CHEMBL3617295

RORATchem NR

EC50 : 7.07

7-ketocholesterol

RORATchem NR

Ki : 7.92

GWAS Traits (49)

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5

1 – 5 of 49

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
serum gamma-glutamyl transferase measurement	EFO_0004532	6	11	13	4.5	99.7
C-reactive protein measurement	EFO_0004458	5	5	7		97.5
asthma	EFO_0000270	8	5	0	1.1	93.7
balding measurement	EFO_0007825	2	6	6		93
allergic rhinitis	EFO_0005854	3	2	0	1.1	87.8

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
serum gamma-glutamyl transferase measurement	EFO_0004532	13	4.5	99.7
C-reactive protein measurement	EFO_0004458	7		97.5
asthma	EFO_0000270	0	1.1	93.7
balding measurement	EFO_0007825	6		93
allergic rhinitis	EFO_0005854	0	1.1	87.8

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Orthologs (12)

1 – 5 of 12

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Macaque	RAR related orphan receptor A		704014
Mouse	RAR-related orphan receptor alpha	MGI:104661	19883
Dog	RAR related orphan receptor A	VGNC:45695	478328
Horse	RAR related orphan receptor A	VGNC:51673	100147460
Cow	RAR related orphan receptor A	VGNC:34088	535597

Species	Name	OMA	EggNOG	Inparanoid
Macaque	RAR related orphan receptor A
Mouse	RAR-related orphan receptor alpha
Dog	RAR related orphan receptor A
Horse	RAR related orphan receptor A
Cow	RAR related orphan receptor A

Protein Structure (3 Structures, 1 AlphaFold Model)

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Representation

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More information can be found at RCSB PDB

AF-P35398-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 3 of 3

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (29)

Reactome (19)

KEGG (3)

PathwayCommons (1)

WikiPathways (6)

Circadian Clock (R-HSA-400253)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Circadian Clock	69 targets	R-HSA-400253
Reactome	Cytokine Signaling in Immune system	922 targets	R-HSA-1280215
Reactome	Gene expression (Transcription)	1452 targets	R-HSA-74160
Reactome	Generic Transcription Pathway	1195 targets	R-HSA-212436
Reactome	Immune System	2246 targets	R-HSA-168256

Name	Explore in Pharos	Explore in Source
Circadian Clock	69 targets	R-HSA-400253
Cytokine Signaling in Immune system	922 targets	R-HSA-1280215
Gene expression (Transcription)	1452 targets	R-HSA-74160
Generic Transcription Pathway	1195 targets	R-HSA-212436
Immune System	2246 targets	R-HSA-168256

Gene Ontology Terms (49)

Functions (16)

Components (2)

Processes (31)

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10

1 – 10 of 16

GO Term	Evidence	Assigned by
DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
DNA-binding transcription factor activity	Inferred from Direct Assay (IDA)	UniProtKB
oxysterol binding	Inferred from Direct Assay (IDA)	UniProtKB
RNA polymerase II proximal promoter sequence-specific DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
RNA polymerase II regulatory region sequence-specific DNA binding	Inferred from Direct Assay (IDA)	MGI
sequence-specific DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
transcription factor activity, direct ligand regulated sequence-specific DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
transcription coactivator binding	Inferred from Physical Interaction (IPI)	UniProtKB
transcription corepressor binding	Inferred from Physical Interaction (IPI)	UniProtKB
transcription factor binding	Inferred from Physical Interaction (IPI)	UniProtKB

Protein-Protein Interactions (89)

Explore Interacting Targets

1 – 10 of 89

• See Interactions on String-DB

ARNTL

Tbio

Family:  TF

Novelty:  0.00102829

Score:  0.985

Data Source:  STRINGDB

NPAS2

Tbio

Family:  TF

Novelty:  0.00728451

Score:  0.978

Data Source:  STRINGDB

CLOCK

Tbio

Family:  TF; Epigenetic

Novelty:  0.00159625

Score:  0.966

Data Source:  STRINGDB

EP300

Tchem

Family:  Epigenetic

Novelty:  0.00055009

Score:  0.958

Data Source:  Reactome,STRINGDB

STAT3

Tchem

Family:  TF

Novelty:  0.00011808

Score:  0.937

Data Source:  STRINGDB

MED1

Tbio

Family:  Enzyme

Novelty:  0.00852082

Score:  0.936

Data Source:  STRINGDB

NRIP1

Tbio

Novelty:  0.00551568

Score:  0.934

Data Source:  Reactome,STRINGDB

NCOR1

Tchem

Family:  TF

Novelty:  0.0021926

Score:  0.927

Data Source:  STRINGDB

NR1D1

Tchem

Family:  NR

Novelty:  0.00250799

Score:  0.926

Data Source:  STRINGDB

HIF1A

Tchem

Family:  TF

Novelty:  0.00011503

Score:  0.924

Data Source:  STRINGDB

Publication Statistics

PubMed Score  243.83

PubMed score by year

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PubTator Score  187.03

PubTator score by year

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

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3D-structure
Activator
Alternative promoter usage
Alternative splicing
Biological rhythms
Complete proteome
Developmental protein
Disease mutation
DNA-binding
Epilepsy

GWAS Trait Find Similar Targets

No Header	No Header
adult onset asthma
age at menarche
age at onset
allergic rhinitis
allergy
Alopecia
apolipoprotein A 1 measurement
aspartate aminotransferase measurement
asthma
balding measurement

MGI Phenotype Find Similar Targets

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behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype
mortality/aging