TheRAR-related orphan receptors (RORs) are members of thenuclear receptor family ofintracellulartranscription factors.[1][2] There are three forms of ROR,ROR-α,-β, and-γ and each is encoded by a separate gene,RORA,RORB, andRORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers tohormone response elements as opposed to the majority of other nuclear receptors which bind as dimers.[3] They bind to DNA elements called ROR response elements (RORE).[4]
While the identity of natural ligands for the RORs remains controversial, similar to theliver X receptors (LXRs), it appears that the RORs are activated byoxysterols.[5][6] Furthermore, the RORs appear to be constitutively active (absence of ligand) and that activity may be due to continuously bound natural ligands.[5] Side chain oxygenated sterols (e.g., 20α-hydroxycholesterol,22R-hydroxycholesterol, and25-hydroxycholesterol) are high affinity RORγ agonists[7] while sterols oxygenated at the 7-position, (e.g., (7-hydroxycholesterol and 7-ketocholesterol) function asinverse agonists for both RORa and RORγ.[5] A number of other natural substances have also been reported to bind to the RORs. These includeall-trans retinoic acid binds with high affinity to ROR-β and -γ but not ROR-α.[8] Finally the RORs may function as lipid sensors and hence may play a role in the regulation of lipid metabolism.[5]
Melatonin has been claimed to be an endogenousligand for ROR-α whileCGP 52608 has been identified as a ROR-α selective synthetic ligand.[9]
A number of synthetic RORγt inverse agonists are in various stages of drug development for the treatment ofinflammatory diseases. RORγt agonists have also been proposed for use asimmunooncology agents to activate the immune system to treat cancer.[13][14]
^Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R (October 2003). "All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta".Nature Structural Biology.10 (10):820–5.doi:10.1038/nsb979.PMID12958591.S2CID10108247.
^Jetten AM (December 2004). "Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs)".Current Drug Targets. Inflammation and Allergy.3 (4):395–412.doi:10.2174/1568010042634497.PMID15584888.
Chang MR, Rosen H, Griffin PR (2014). "RORs in Autoimmune Disease".Sphingosine-1-Phosphate Signaling in Immunology and Infectious Diseases. Current Topics in Microbiology and Immunology. Vol. 378. pp. 171–82.doi:10.1007/978-3-319-05879-5_8.ISBN978-3-319-05878-8.PMID24728598.
