Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [1]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol [5-6].

Tretinoin shows selectivity for RORβ within the ROR family [8]. RORα has been suggested to be a nuclear receptor responding to melatonin [10].

* Key recommended reading is highlighted with an asterisk

* Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev., 58 (4): 798-836. [PMID:17132856]

* Cyr P, Bronner SM, Crawford JJ. (2016) Recent progress on nuclear receptor RORγ modulators. Bioorg. Med. Chem. Lett., 26 (18): 4387-4393. [PMID:27542308]

* Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev., 58 (4): 685-704. [PMID:17132848]

* Guillemot-Legris O, Mutemberezi V, Muccioli GG. (2016) Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids. Trends Mol Med, 22 (7): 594-614. [PMID:27286741]

Kojetin DJ, Burris TP. (2014) REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov, 13 (3): 197-216. [PMID:24577401]

Marciano DP, Chang MR, Corzo CA, Goswami D, Lam VQ, Pascal BD, Griffin PR. (2014) The therapeutic potential of nuclear receptor modulators for treatment of metabolic disorders: PPARγ, RORs, and Rev-erbs. Cell Metab., 19 (2): 193-208. [PMID:24440037]

* Mutemberezi V, Guillemot-Legris O, Muccioli GG. (2016) Oxysterols: From cholesterol metabolites to key mediators. Prog. Lipid Res., 64: 152-169. [PMID:27687912]

Wu D, Cheung A, Wang Y, Yu S, Chan FL. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim. Biophys. Acta, 1866 (1): 23-36. [PMID:27264242]

Zhang Y, Luo XY, Wu DH, Xu Y. (2015) ROR nuclear receptors: structures, related diseases, and drug discovery. Acta Pharmacol. Sin., 36 (1): 71-87. [PMID:25500868]

1. Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev., 58 (4): 798-836. [PMID:17132856]

2. Bitsch F, Aichholz R, Kallen J, Geisse S, Fournier B, Schlaeppi JM. (2003) 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., 323 (1): 139-49. [PMID:14622968]

3. Eberl G, Littman DR. (2004) Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Science, 305 (5681): 248-51. [PMID:15247480]

4. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. (2004) An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol., 5 (1): 64-73. [PMID:14691482]

5. Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B. (2004) Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. J. Biol. Chem., 279 (14): 14033-8. [PMID:14722075]

6. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. (2002) 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, 10 (12): 1697-707. [PMID:12467577]

7. Paravicini G, Steinmayr M, André E, Becker-André M. (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem. Biophys. Res. Commun., 227 (1): 82-7. [PMID:8858107]

8. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R. (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol., 10 (10): 820-5. [PMID:12958591]

9. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR. (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science, 288 (5475): 2369-73. [PMID:10875923]

10. Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C. (1995) Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Res., 23 (3): 327-33. [PMID:7885826]

Subcommittee members: Anton Jetten, Ph.D. Cell Biology Section Immunity, Inflammation and Disease Laboratory NIEHS/NIH 111 TW Alexander Dr. Research Triangle Park, NC 27709, USA Hong Soon Kang Cell Biology Section Immunity, Inflammation and Disease Laboratory NIEHS/NIH 111 TW Alexander Dr. Research Triangle Park, NC 27709, USA Yukimasa Takeda Cell Biology Section Immunity, Inflammation and Disease Laboratory NIEHS/NIH 111 TW Alexander Dr. Research Triangle Park, NC 27709, USA