Target Information
Target General Information | Top | |||||
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Target ID |
T43206
(Former ID: TTDR00593)
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Target Name |
Nuclear receptor ROR-alpha (RORA)
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Synonyms |
Retinoid-related orphan receptor-alpha; Retinoic acid-related orphan receptor alpha; RZRA; RAR-related orphan receptor A; Nuclear receptor subfamily 1 group F member 1; Nuclear receptor RZR-alpha; NR1F1
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Gene Name |
RORA
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Target Type |
Preclinical target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Liver cancer [ICD-11: 2C12] | |||||
2 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
Function |
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, 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. 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.
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BioChemical Class |
Nuclear hormone receptor
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UniProt ID | ||||||
Sequence |
MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSSTSRGISVT
KKTHTSQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRT SRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAE PLTPTYNISANGLTELHDDLSNYIDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIK PEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITW QTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQNDQIVLLKAGS LEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEI ALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRAL CGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T61M4P |
Drugs and Modes of Action | Top | |||||
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Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
1 | SR1078 | Drug Info | Preclinical | Liver cancer | [2] | |
2 | SR3335 | Drug Info | Preclinical | Type-2 diabetes | [2] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 1 Inhibitor drugs | + | ||||
1 | US9598431, 3 | Drug Info | [3] | |||
Agonist | [+] 3 Agonist drugs | + | ||||
1 | SR1078 | Drug Info | [4] | |||
2 | SR3335 | Drug Info | [5] | |||
3 | 7-hydroxycholesterol | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: Cholesterol | Ligand Info | |||||
Structure Description | Crystal Structure of the complex between the Orphan Nuclear Hormone Receptor ROR(alpha)-LBD and Cholesterol | PDB:1N83 | ||||
Method | X-ray diffraction | Resolution | 1.63 Å | Mutation | No | [6] |
PDB Sequence |
HHLEVLFQGP
270 AELEHLAQNI280 SKSHLETCQY290 LREELQQITW300 QTFLQEEIEN310 YQNKQREVMW 320 QLCAIKITEA330 IQYVVEFAKR340 IDGFMELCQN350 DQIVLLKAGS360 LEVVFIRMCR 370 AFDSQNNTVY380 FDGKYASPDV390 FKSLGCEDFI400 SFVFEFGKSL410 CSMHLTEDEI 420 ALFSAFVLMS430 ADRSWLQEKV440 KIEKLQQKIQ450 LALQHVLQKN460 HREDGILTKL 470 ICKVSTLRAL480 CGRHTEKLMA490 FKAIYPDIVR500 LHFPPLYKEL510 F |
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TRP320
3.509
CYS323
3.976
ALA324
4.850
LYS326
3.473
ILE327
3.674
ALA330
3.687
VAL364
3.620
PHE365
4.065
ARG367
3.778
MET368
3.633
ARG370
4.872
ALA371
4.145
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Ligand Name: Cholesterol sulfate | Ligand Info | |||||
Structure Description | Crystal structure of the human RORalpha ligand binding domain in complex with cholesterol sulfate at 2.2A | PDB:1S0X | ||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [7] |
PDB Sequence |
HHLEVLFQGP
270 AELEHLAQNI280 SKSHLETCQY290 LREELQQITW300 QTFLQEEIEN310 YQNKQREVMW 320 QLCAIKITEA330 IQYVVEFAKR340 IDGFMELCQN350 DQIVLLKAGS360 LEVVFIRMCR 370 AFDSQNNTVY380 FDGKYASPDV390 FKSLGCEDFI400 SFVFEFGKSL410 CSMHLTEDEI 420 ALFSAFVLMS430 ADRSWLQEKV440 KIEKLQQKIQ450 LALQHVLQKN460 HREDGILTKL 470 ICKVSTLRAL480 CGRHTEKLMA490 FKAIYPDIVR500 LHFPPLYKEL510 F |
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THR287
4.889
CYS288
3.662
GLN289
2.993
TYR290
2.876
LEU295
4.392
TRP320
3.216
CYS323
3.477
ALA324
3.909
LYS326
3.748
ILE327
3.842
ALA330
3.840
TYR333
4.747
VAL364
3.915
PHE365
4.432
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Th17 cell differentiation | hsa04659 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
Circadian rhythm | hsa04710 | Affiliated Target |
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Class: Organismal Systems => Environmental adaptation | Pathway Hierarchy |
Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 3.42E-05 |
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Closeness centrality | 2.00E-01 | Radiality | 1.35E+01 | Clustering coefficient | 1.33E-01 |
Neighborhood connectivity | 1.60E+01 | Topological coefficient | 2.50E-01 | Eccentricity | 11 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Circadian rhythm | |||||
2 | Inflammatory bowel disease (IBD) | |||||
NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
1 | IL2 Signaling Pathway | |||||
Reactome | [+] 5 Reactome Pathways | + | ||||
1 | RORA activates gene expression | |||||
2 | BMAL1:CLOCK,NPAS2 activates circadian gene expression | |||||
3 | PPARA activates gene expression | |||||
4 | Nuclear Receptor transcription pathway | |||||
5 | Circadian Clock | |||||
WikiPathways | [+] 5 WikiPathways | + | ||||
1 | SIDS Susceptibility Pathways | |||||
2 | Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) | |||||
3 | Adipogenesis | |||||
4 | Circadian Clock | |||||
5 | Nuclear Receptors |
References | Top | |||||
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REF 1 | Identification of natural ligands of retinoic acid receptor-related orphan receptor alpha ligand-binding domain expressed in Sf9 cells--a mass spectrometry approach. Anal Biochem. 2003 Dec 1;323(1):139-49. | |||||
REF 2 | Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021 Apr;20(4):287-307. | |||||
REF 3 | Compounds useful for inhibiting ROR-gamma-t. US9598431. | |||||
REF 4 | Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and ROR. ACS Chem Biol. 2010 Nov 19;5(11):1029-34. | |||||
REF 5 | Identification of SR3335 (ML-176): a synthetic RORalpha selective inverse agonist. ACS Chem Biol. 2011 Mar 18;6(3):218-22. | |||||
REF 6 | X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure. 2002 Dec;10(12):1697-707. | |||||
REF 7 | Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem. 2004 Apr 2;279(14):14033-8. |
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