Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGQT12P)

• DOT Name: Nuclear receptor ROR-alpha (RORA)
• Synonyms: Nuclear receptor RZR-alpha; Nuclear receptor subfamily 1 group F member 1; RAR-related orphan receptor A; Retinoid-related orphan receptor-alpha
• Gene Name: RORA
• Related Disease:
  Intellectual developmental disorder with or without epilepsy or cerebellar ataxia
  Intellectual disability, autosomal dominant 40
• UniProt ID: RORA_HUMAN
• PDB ID: 1N83; 1S0X; 4S15
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSSTSRGISVT
  KKTHTSQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRT
  SRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAE
  PLTPTYNISANGLTELHDDLSNYIDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIK
  PEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITW
  QTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQNDQIVLLKAGS
  LEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEI
  ALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRAL
  CGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG
• Function: 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. 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, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as 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 G6PC1 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.
• Tissue Specificity: Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff) . Isoform 4: Highly expressed in the central nervous system, including in the cerebellum .
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Circadian rhythm (hsa04710)
  Spinocerebellar ataxia (hsa05017)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Circadian Clock (R-HSA-400253)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	DISR3K8S	Strong	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[2]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nuclear receptor ROR-alpha (RORA).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nuclear receptor ROR-alpha (RORA).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Nuclear receptor ROR-alpha (RORA).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nuclear receptor ROR-alpha (RORA).	[25]

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor ROR-alpha (RORA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear receptor ROR-alpha (RORA).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear receptor ROR-alpha (RORA).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor ROR-alpha (RORA).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear receptor ROR-alpha (RORA).	[8]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Nuclear receptor ROR-alpha (RORA).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nuclear receptor ROR-alpha (RORA).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear receptor ROR-alpha (RORA).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Nuclear receptor ROR-alpha (RORA).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nuclear receptor ROR-alpha (RORA).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Nuclear receptor ROR-alpha (RORA).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Nuclear receptor ROR-alpha (RORA).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nuclear receptor ROR-alpha (RORA).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate increases the expression of Nuclear receptor ROR-alpha (RORA).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Nuclear receptor ROR-alpha (RORA).	[19]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Nuclear receptor ROR-alpha (RORA).	[20]
Chenodiol	DMQ8JIK	Approved	Chenodiol affects the expression of Nuclear receptor ROR-alpha (RORA).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor ROR-alpha (RORA).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Nuclear receptor ROR-alpha (RORA).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nuclear receptor ROR-alpha (RORA).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear receptor ROR-alpha (RORA).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nuclear receptor ROR-alpha (RORA).	[27]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Nuclear receptor ROR-alpha (RORA).	[28]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol affects the binding of Nuclear receptor ROR-alpha (RORA).	[29]
M-Phenoxybenzoic Acid For Cis-Isomer	DMJRK47	Investigative	M-Phenoxybenzoic Acid For Cis-Isomer affects the binding of Nuclear receptor ROR-alpha (RORA).	[30]

References

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