Target Information
Target General Information | Top | |||||
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Target ID |
T00254
(Former ID: TTDI03516)
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Target Name |
V-erbA-related protein 1 (NR1D1)
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Synonyms |
THRAL; Rev-erbA-alpha; Nuclear receptor subfamily 1 group D member 1; HREV; EAR1; EAR-1
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Gene Name |
NR1D1
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Target Type |
Preclinical target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Cardiomyopathy [ICD-11: BC43] | |||||
2 | Postoperative inflammation [ICD-11: 1A00-CA43] | |||||
3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity).
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UniProt ID | ||||||
Sequence |
MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSL
TQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTS NITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNENCSIVRI NRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLSSQCPLETS PTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTVEDVISQVARAHREIF TYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAAQRHNEALNGLRQ APSSYPPTWPPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSPRQGNSKNVLLACPM NMYPHGRSGRTVQEIWEDFSMSFTPAVREVVEFAKHIPGFRDLSQHDQVTLLKAGTFEVL MVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFDFSEKLNSLALTEEELGLF TAVVLVSADRSGMENSASVEQLQETLLRALRALVLKNRPLETSRFTKLLLKLPDLRTLNN MHSEKLLSFRVDAQ Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Preclinical Drug(s) | [+] 4 Preclinical Drugs | + | ||||
1 | GSK4112 | Drug Info | Preclinical | Inflammation | [2] | |
2 | SR8278 | Drug Info | Preclinical | Myocardial disease | [2] | |
3 | SR9009 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
4 | SR9011 | Drug Info | Preclinical | Solid tumour/cancer | [2] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Agonist | [+] 3 Agonist drugs | + | ||||
1 | GSK4112 | Drug Info | [1] | |||
2 | SR9009 | Drug Info | [3] | |||
3 | SR9011 | Drug Info | [3] | |||
Antagonist | [+] 1 Antagonist drugs | + | ||||
1 | SR8278 | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
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 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 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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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Circadian rhythm | hsa04710 | Affiliated Target |
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Class: Organismal Systems => Environmental adaptation | Pathway Hierarchy |
Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 2.22E-05 |
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Closeness centrality | 2.13E-01 | Radiality | 1.37E+01 | Clustering coefficient | 4.29E-01 |
Neighborhood connectivity | 2.58E+01 | Topological coefficient | 2.03E-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 |
References | Top | |||||
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REF 1 | Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem Biol. 2011 Feb 18;6(2):131-4. | |||||
REF 2 | Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021 Apr;20(4):287-307. | |||||
REF 3 | Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 2018 Jan 18;553(7688):351-355. |
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