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Retinoid X receptor-γ

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Target not currently curated in GtoImmuPdb

Target id: 612

Nomenclature: Retinoid X receptor-γ

Systematic Nomenclature: NR2B3

Family: 2B. Retinoid X receptors

Contents:

Gene and Protein Information Click here for help
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 463 1q23.3 RXRG retinoid X receptor gamma 2,23
Mouse 463 1 74.99 cM Rxrg retinoid X receptor gamma 14,19-20,23
Rat 463 13q24 Rxrg retinoid X receptor gamma 3
Previous and Unofficial Names Click here for help
nuclear receptor subfamily 2 group B member 3 | retinoic acid receptor RXR-gamma | retinoid X receptor, gamma | RXRγ
Database Links Click here for help
Alphafold P48443 (Hs), P28705 (Mm), Q5BJR8 (Rn)
CATH/Gene3D 3.30.50.10
ChEMBL Target CHEMBL2004 (Hs), CHEMBL4402 (Mm), CHEMBL4277 (Rn)
DrugBank Target P48443 (Hs)
Ensembl Gene ENSG00000143171 (Hs), ENSMUSG00000015843 (Mm), ENSRNOG00000004537 (Rn)
Entrez Gene 6258 (Hs), 20183 (Mm), 83574 (Rn)
Human Protein Atlas ENSG00000143171 (Hs)
KEGG Gene hsa:6258 (Hs), mmu:20183 (Mm), rno:83574 (Rn)
OMIM 180247 (Hs)
Pharos P48443 (Hs)
RefSeq Nucleotide NM_006917 (Hs), NM_001159731 (Mm), NM_009107 (Mm), NM_031765 (Rn)
RefSeq Protein NP_008848 (Hs), NP_001153203 (Mm), NP_033133 (Mm), NP_113953 (Rn)
UniProtKB P48443 (Hs), P28705 (Mm), Q5BJR8 (Rn)
Wikipedia RXRG (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  RXR-gamma - ligand-binding domain (Apostructure)
PDB Id:  2GL8
Resolution:  2.4Å
Species:  Human
References: 
Natural/Endogenous Ligands Click here for help
alitretinoin

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AGN194204 Small molecule or natural product N/A Agonist 8.4 pKd 32
⤷ pKd 8.4 [32]
[3H]9-cis-retinoic acid Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Mm Full agonist 7.9 pKd 1
⤷ pKd 7.9 (Kd 1.41x10-8 M) [1]
compound 28 [Heitel et al., 2019] Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.8 pEC50 12
⤷ pEC50 5.8 (EC50 1.6x10-6 M) [12]
LG100268 Small molecule or natural product Ligand has a PDB structure N/A Agonist 8.0 – 8.5 pIC50 4,17,29
⤷ pIC50 8.0 – 8.5 [4,17,29]
bexarotene Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 7.5 pIC50 5,7,29
⤷ pIC50 7.5 [5,7,29]
alitretinoin Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 7.0 – 8.0 pIC50 1,13,17,21,23,27
⤷ pIC50 7.0 – 8.0 [1,13,17,21,23,27]
View species-specific agonist tables
Antagonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LG100754 Small molecule or natural product Ligand has a PDB structure N/A Antagonist 7.9 pKi 17
⤷ pKi 7.9 (Ki 1.22x10-8 M) [17]
DNA Binding Click here for help
Structure:  Homodimer, Heterodimer, RXR partner
HRE core sequence:  5’-AGGTCA
Response element:  DR1, DR2, DR3, DR4, DR5
DNA Binding Comments
RXR can bind to several DR elements as common heterodimerization partners for members of the subfamily 1 of nuclear receptors. In direct repeats, RXR generally occupies the 5’-element. RXR can also form RXR-RXR homodimers that bind to DR1.
Name Interaction Effect Reference
Co-binding Partners Comments
Binding partners are the same as RXRα.
Main Co-regulators Click here for help
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No Yes Yes 18,26,28
NCOA2 Co-activator No Yes Yes 18,30-31
NCOA3 Co-activator No Yes Yes 8,18,26
Tissue Distribution Click here for help
Muscle, brain
Species:  Mouse
Technique:  Northern, in situ, Western, other
References:  9-11,22-23
Tissue Distribution Comments
RXRγ displays the highest restricted expression pattern of the three RXRs.The RXRγ1 isoform is expressed in brain and muscle, whereas RXRγ2 is highly expressed in both cardiac and skeletal muscles. Similar expression pattern observed in the rat.
Physiological Consequences of Altering Gene Expression Click here for help
Knockout mice are viable and fertile but show metabolic and behavorial defects.
Species:  Mouse
Tissue: 
Technique:  Knockout by homologous recombination in embryonic stem cells
References:  6,15-16,24-25
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Rxrgtm1Ysa Rxrgtm1Ysa/Rxrgtm1Ysa
either: (involves: 129S2/SvPas * C57BL/6) or (involves: 129S2/SvPas * C57BL/6 * ICR)		 MGI:98216  MP:0004077 abnormal striatum morphology PMID: 10336693 
Rxrgtm2Ysa Rxrgtm2Ysa/Rxrgtm2Ysa
involves: C57BL/6 * CBA		 MGI:98216  MP:0004077 abnormal striatum morphology PMID: 10336693 
Rxrgtm1Ysa Rxrgtm1Ysa/Rxrgtm1Ysa
either: (involves: 129S2/SvPas * C57BL/6) or (involves: 129S2/SvPas * C57BL/6 * ICR)		 MGI:98216  MP:0002822 catalepsy PMID: 10336693 
Rxrgtm1Ysa Rxrgtm1Ysa/Rxrgtm1Ysa
B6.129S2-Rxrg		 MGI:98216  MP:0004037 increased muscle relaxation PMID: 10336693 
Rxrgtm1Ipc Rxrgtm1Ipc/Rxrgtm1Ipc
involves: 129S2/SvPas		 MGI:98216  MP:0002169 no abnormal phenotype detected PMID: 8799145 
Rxrgtm1Ysa Rxrgtm1Ysa/Rxrgtm1Ysa
either: (involves: 129S2/SvPas * C57BL/6) or (involves: 129S2/SvPas * C57BL/6 * ICR)		 MGI:98216  MP:0002083 premature death PMID: 10336693 

References

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1. Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P. (1993) Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA, 90 (1): 30-4. [PMID:8380496]

2. Almasan A, Mangelsdorf DJ, Ong ES, Wahl GM, Evans RM. (1994) Chromosomal localization of the human retinoid X receptors. Genomics, 20 (3): 397-403. [PMID:8034312]

3. Belanger AJ, Luo Z, Vincent KA, Akita GY, Cheng SH, Gregory RJ, Jiang C. (2007) Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor alpha/retinoid X receptor. Biochem Biophys Res Commun, 364 (3): 567-72. [PMID:17963722]

4. Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, Winn D, Goldman ME, Heyman RA. (1994) Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties. J Med Chem, 37 (3): 408-14. [PMID:8308867]

5. Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA. (1994) Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem, 37 (18): 2930-41. [PMID:8071941]

6. Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, Haugen BR. (2000) Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse. J Clin Invest, 106 (1): 73-9. [PMID:10880050]

7. Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM. (1999) Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells. J Med Chem, 42 (4): 742-50. [PMID:10052980]

8. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM. (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell, 90 (3): 569-80. [PMID:9267036]

9. Chiang MY, Misner D, Kempermann G, Schikorski T, Giguère V, Sucov HM, Gage FH, Stevens CF, Evans RM. (1998) An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. Neuron, 21 (6): 1353-61. [PMID:9883728]

10. Dollé P, Fraulob V, Kastner P, Chambon P. (1994) Developmental expression of murine retinoid X receptor (RXR) genes. Mech Dev, 45 (2): 91-104. [PMID:8199055]

11. Haugen BR, Brown NS, Wood WM, Gordon DF, Ridgway EC. (1997) The thyrotrope-restricted isoform of the retinoid-X receptor-gamma1 mediates 9-cis-retinoic acid suppression of thyrotropin-beta promoter activity. Mol Endocrinol, 11 (4): 481-9. [PMID:9092800]

12. Heitel P, Gellrich L, Kalinowsky L, Heering J, Kaiser A, Ohrndorf J, Proschak E, Merk D. (2019) Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X Receptor Agonist Chemotype. ACS Med Chem Lett, 10 (2): 203-208. DOI: 10.1021/acsmedchemlett.8b00551 [PMID:30783504]

13. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C. (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell, 68 (2): 397-406. [PMID:1310260]

14. Hoopes CW, Taketo M, Ozato K, Liu Q, Howard TA, Linney E, Seldin MF. (1992) Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXR alpha, RXR beta, and RXR gamma. Genomics, 14 (3): 611-7. [PMID:1358808]

15. Krezel W, Dupé V, Mark M, Dierich A, Kastner P, Chambon P. (1996) RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable. Proc Natl Acad Sci USA, 93 (17): 9010-4. [PMID:8799145]

16. Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E, Chambon P. (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science, 279 (5352): 863-7. [PMID:9452386]

17. Lala DS, Mukherjee R, Schulman IG, Koch SS, Dardashti LJ, Nadzan AM, Croston GE, Evans RM, Heyman RA. (1996) Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature, 383 (6599): 450-3. [PMID:8837780]

18. Laudet V, Gronemeyer H. (2002) The Nuclear Receptor Facts Book. In The Nuclear Receptor Facts Book. (Academic Press) .

19. Leid M, Kastner P, Chambon P. (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci, 17 (10): 427-33. [PMID:1333659]

20. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S. (1992) Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell, 68 (2): 377-95. [PMID:1310259]

21. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A. (1992) 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature, 355 (6358): 359-61. [PMID:1309942]

22. Liu Q, Linney E. (1993) The mouse retinoid-X receptor-gamma gene: genomic organization and evidence for functional isoforms. Mol Endocrinol, 7 (5): 651-8. [PMID:8391126]

23. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. (1992) Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev, 6 (3): 329-44. [PMID:1312497]

24. Mark M, Chambon P. (2003) Functions of RARs and RXRs in vivo: genetic dissection of the retinoid signaling pathway. Pure Appl Chem, 75: 1709-1732.

25. Mark M, Ghyselinck NB, Chambon P. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol, 46: 451-80. [PMID:16402912]

26. McKenna NJ, Lanz RB, O'Malley BW. (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev, 20 (3): 321-44. [PMID:10368774]

27. Nagy L, Thomázy VA, Shipley GL, Fésüs L, Lamph W, Heyman RA, Chandraratna RA, Davies PJ. (1995) Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol, 15 (7): 3540-51. [PMID:7791761]

28. Oñate SA, Tsai SY, Tsai MJ, O'Malley BW. (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science, 270 (5240): 1354-7. [PMID:7481822]

29. Thacher SM, Vasudevan J, Chandraratna RA. (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des, 6 (1): 25-58. [PMID:10637371]

30. Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. (1998) The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J, 17 (2): 507-19. [PMID:9430642]

31. Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H. (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J, 15 (14): 3667-75. [PMID:8670870]

32. Vuligonda V, Thacher SM, Chandraratna RA. (2001) Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes. J Med Chem, 44 (14): 2298-303. [PMID:11428923]

How to cite this page

2B. Retinoid X receptors: Retinoid X receptor-γ. Last modified on 23/04/2019. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=612.