Rev-Erb-β | 1D. Rev-Erb receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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Target not currently curated in GtoImmuPdb

Target id: 597

Nomenclature: Rev-Erb-β

Systematic Nomenclature: NR1D2

Family: 1D. Rev-Erb receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 579 3p24.2 NR1D2 nuclear receptor subfamily 1 group D member 2 3
Mouse 576 14B Nr1d2 nuclear receptor subfamily 1 5,10
Rat 494 15p16 Nr1d2 nuclear receptor subfamily 1 6,13
Previous and Unofficial Names
HZF2 | EAR-1r | EAR4 | orphan nuclear receptor HZF-2 | nuclear receptor subfamily 1
Database Links
Specialist databases
NURSA Receptor 10.1621/MHWSORHQO1 (Hs)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Rev-Erbβ- apostructure
PDB Id:  2V0V
Resolution:  2.4Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Rev-Erbβ in complex with heme
Resolution:  1.9Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ligand binding domain (LBD) of REV-ERB beta bound to Cobalt Protoporphyrin IX.
PDB Id:  4N73
Ligand:  cobalt protoporphyrin IX
Resolution:  1.87Å
Species:  Human
References:  8
Natural/Endogenous Ligands
Comments: Orphan

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
heme Hs Agonist 6.4 pKd 8,11,17
pKd 6.4 (Kd 3.53x10-7 M) [8,11,17]
SR9011 Hs Agonist 6.3 pIC50 15
pIC50 6.3 (IC50 5.6x10-7 M) [15]
SR9009 Hs Agonist 6.1 pIC50 15
pIC50 6.1 (IC50 8x10-7 M) [15]
Agonist Comments
No ligand identified. Homology modeling of the putative LBDs of the NR1D subgroup suggested that the pocket is occupied by bulky side chains, and the small residual cavity could not accommodate a classical ligand [12].
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
cobalt protoporphyrin IX Hs Antagonist 5.6 pKd 8
pKd 5.6 (Kd 2.56x10-6 M) [8]
zinc protoporphyrin IX Hs Antagonist - - 8
Description: Increases transcription by inhibiting corepressor recruitment to REV-ERB in vitro.
DNA Binding
Structure:  Monomer, Homodimer
HRE core sequence:  A/T A A/T N T PuGGTCA
Response element:  DR2, Half site
DNA Binding Comments
The Rev-erbβ gene product has been shown to bind to DNA as a monomer to RevRE (response element) which contains an AGGTCA motif linked in 5’ to an A/T rich sequence harbouring the following consensus : A/T A A/T N T. Later on, it was shown by site selection experiments as well as by the study of a natural RevRE found in the human Rev-erbβ promoter that it is able to homodimerize on RevDR2 elements that are composed of one classical RevRE followed in 3’ by an AGGTCA motif. The two motifs are separated by two bases that are always a C and a T. Much of this information is inferred from studies of Rev-erbα.
Co-binding Partners
Name Interaction Effect Reference
Rev-erbb Physical, Functional DNA binding 7
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOR1 Co-repressor No No No 1-2
NCOA5 Other No No No This cofactor encompasses both coactivator and corepressor functions. 14
Main Target Genes
Name Species Effect Technique Comments References
NDRG1 Human Repressed Transient transfection, EMSA NDRG1 (N-Myc) has the same effect in the mouse and rat. 4
NR1D1 Human Repressed Transient transfection, EMSA, Other 4
Tissue Distribution
Species:  Human
Technique:  in situ hybridization, Immunohistology, Northern Blot, Q-PCR, Western blotting
References:  3,5-6,13
Tissue Distribution Comments
Rev-erbβ is found as two transcripts of 5.5 and 4 kb in rat and only one at 4.5 kb in human and mouse. In all mammals examined this gene is expressed in a wide variety of tissues such as heart, brain, lung, liver, skeletal muscles and kidney. Very weak expression was observed in spleen and testis. In situ hybridisation experiments reveals a strong expression in the central nervous system in the cerebellar cortex as well as in the dentate gyrus and in the hippocampus.


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1. Burke LJ, Downes M, Laudet V, Muscat GE. (1998) Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. Mol. Endocrinol., 12 (2): 248-62. [PMID:9482666]

2. Downes M, Burke LJ, Bailey PJ, Muscat GE. (1996) Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors. Nucleic Acids Res., 24 (22): 4379-86. [PMID:8948627]

3. Dumas B, Harding HP, Choi HS, Lehmann KA, Chung M, Lazar MA, Moore DD. (1994) A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb. Mol. Endocrinol., 8 (8): 996-1005. [PMID:7997240]

4. Dussault I, Giguère V. (1997) Differential regulation of the N-myc proto-oncogene by ROR alpha and RVR, two orphan members of the superfamily of nuclear hormone receptors. Mol. Cell. Biol., 17 (4): 1860-7. [PMID:9121434]

5. Enmark E, Kainu T, Pelto-Huikko M, Gustafsson JA. (1994) Identification of a novel member of the nuclear receptor superfamily which is closely related to Rev-ErbA. Biochem. Biophys. Res. Commun., 204 (1): 49-56. [PMID:7945391]

6. Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM. (1994) Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. Mol. Endocrinol., 8 (9): 1253-61. [PMID:7838158]

7. Harding HP, Lazar MA. (1995) The monomer-binding orphan receptor Rev-Erb represses transcription as a dimer on a novel direct repeat. Mol. Cell. Biol., 15 (9): 4791-802. [PMID:7651396]

8. Matta-Camacho E, Banerjee S, Hughes TS, Solt LA, Wang Y, Burris TP, Kojetin DJ. (2014) Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist. J. Biol. Chem., 289 (29): 20054-66. [PMID:24872411]

9. Pardee KI, Xu X, Reinking J, Schuetz A, Dong A, Liu S, Zhang R, Tiefenbach J, Lajoie G, Plotnikov AN, Botchkarev A, Krause HM, Edwards A. (2009) The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. PLoS Biol., 7 (2): e43. [PMID:19243223]

10. Peña de Ortiz S, Cannon MM, Jamieson GA. (1994) Expression of nuclear hormone receptors within the rat hippocampus: identification of novel orphan receptors. Brain Res. Mol. Brain Res., 23 (3): 278-83. [PMID:7914660]

11. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. (2007) Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat. Struct. Mol. Biol., 14 (12): 1207-13. [PMID:18037887]

12. Renaud JP, Harris JM, Downes M, Burke LJ, Muscat GE. (2000) Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. Mol. Endocrinol., 14 (5): 700-17. [PMID:10809233]

13. Retnakaran R, Flock G, Giguère V. (1994) Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. Mol. Endocrinol., 8 (9): 1234-44. [PMID:7838156]

14. Sauvé F, McBroom LD, Gallant J, Moraitis AN, Labrie F, Giguère V. (2001) CIA, a novel estrogen receptor coactivator with a bifunctional nuclear receptor interacting determinant. Mol. Cell. Biol., 21 (1): 343-53. [PMID:11113208]

15. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R et al.. (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature, 485 (7396): 62-8. [PMID:22460951]

16. Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Ryu SE. (2007) Structural insight into the constitutive repression function of the nuclear receptor Rev-erbbeta. J. Mol. Biol., 373 (3): 735-44. [PMID:17870090]

17. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB et al.. (2007) Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science, 318 (5857): 1786-9. [PMID:18006707]

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1D. Rev-Erb receptors: Rev-Erb-β. Last modified on 05/11/2015. Accessed on 20/03/2019. IUPHAR/BPS Guide to PHARMACOLOGY,