RAR-related orphan receptor alpha
RAR-related orphan receptor alpha (ROR), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a nuclear receptor that in humans is encoded by the RORA gene. ROR participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, ROR is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.  In addition, although present in normal numbers, the  ILC3 and Th17 cells from ROR deficient mice are defective for cytokine production.

# Discovery
The first three human isoforms of ROR were initially cloned and characterized as nuclear receptors in 1994 by Giguere and colleagues, when their structure and function were first studied.
In the early 2000s, various studies demonstrated that ROR displays rhythmic patterns of expression in a circadian cycle in the liver, kidney, retina, and lung. Of interest, it was around this time that ROR abundance was found to be circadian in the mammalian suprachiasmatic nucleus. ROR is necessary for normal circadian rhythms in mice, demonstrating its importance in chronobiology.

# Structure
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. In humans, 4 isoforms of ROR have been identified, which are generated via alternative splicing and promoter usage, and exhibit differential tissue-specific expression. The protein structure of ROR consists of four canonical functional groups: an N-terminal (A/B) domain, a DNA-binding domain containing two zinc fingers, a hinge domain, and a C-terminal ligand-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved. Different isoforms of ROR have different binding specificities and strengths of transcriptional activity.

# Regulation of circadian rhythm
The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock. This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1. Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB Response Element (RRE) in the Bmal1 promoter, to which ROR and REV-ERB bind. This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of ROR and REV-ERB. ROR, which activates transcription of Bmal1, and REV-ERB, which represses transcription of Bmal1, compete to bind to the RRE. This feedback loop regulating the expression of Bmal1 is thought to stabilize the core clock mechanism, helping to buffer it against changes in the environment.

# Mechanism
Specific association with ROR elements (RORE) in regulatory regions is necessary for RORs function as a transcriptional activator. ROR achieves this by specific binding to a consensus core motif in RORE, RGGTCA. This interaction is possible through the association of RORs first zinc finger with the core motif in the major groove, the P-box, and the association of its C-terminal extension with the AT-rich region in the 5 region of RORE.

# Homology
ROR, ROR, and ROR are all transcriptional activators recognizing ROR-response elements. ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development. The ROR isoforms (ROR1 through ROR3) arise via alternative RNA processing, with ROR2 and ROR3 sharing an amino-terminal region different from ROR1. In contrast to ROR, ROR is expressed in Central Nervous System (CNS) tissues involved in processing sensory information and in generating circadian rhythms while ROR is critical in lymph node organogenesis and thymopoeisis.
The DNA-binding domains of the DHR3 orphan receptor in Drosophila shows especially close homology within amino and carboxy regions adjacent to the second zinc finger region in ROR, suggesting that this group of residues is important for the proteins' functionalities.
PDP1 and VRI in Drosophila regulate circadian rhythm's by competing for the same binding site, the VP box, similarly to how ROR and REV-ERB competitively bind to RRE. PDP1 and VRI constitute a feedback loop and are functional homologs of ROR and REV-ERB in mammals.
Direct orthologs of this gene have been identified in mice and humans.
Human cytochrome c pseudogene HC2 and ROR share overlapping genomic organization with the HC2 pseudogene located within the ROR2 transcription unit. The nucleotide and deduced amino acid sequences of cytochrome c-processed pseudogene are on the sense strand while those of the ROR2 amino-terminal exon are on the antisense strand.

# Interactions
- DNA: ROR binds to the P-box of the RORE.
- Co-activators:
SRC-1, CBP, p300, TRIP-l, TRIP-230, transcription intermediary protein-1 (TIF-1), peroxisome proliferator-binding protein (PBP), and GRIP-1 physically interact with ROR.
LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.
- SRC-1, CBP, p300, TRIP-l, TRIP-230, transcription intermediary protein-1 (TIF-1), peroxisome proliferator-binding protein (PBP), and GRIP-1 physically interact with ROR.
LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.
- LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.
- Ubiquitination: ROR is targeted for the proteasome by ubiquitination. A co-repressor, Hairless, stabilizes ROR by protecting it from this process, which also represses ROR.
- Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.
- Phosphorylation:
Phosphorylation of ROR1, which inhibits its transcriptional activity, is induced by Protein Kinase C.
ERK2: Extracellular signal-regulated kinase-2 also phosphorylates ROR.
- Phosphorylation of ROR1, which inhibits its transcriptional activity, is induced by Protein Kinase C.
- ERK2: Extracellular signal-regulated kinase-2 also phosphorylates ROR.
- ATXN1: ATXN1 and ROR form part of a protein complex in Purkinje cells.
- FOXP3: FOXP3 directly represses the transcriptional activity of RORs.
- NME1: ROR has been shown to specifically interact with NME1.
- NM23-2: NM23-2 is a nucleoside diphosphate kinase involved in organogenesis and differentiation.
- NM23-1: NM23-1 is the product of a tumor metastasis suppressor candidate gene.

# As a drug target
Because ROR and REV-ERB are nuclear receptors that share the same target genes and are involved in processes that regulate metabolism, development, immunity, and circadian rhythm, they show potential as drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as diabetes, atherosclerosis, autoimmunity, and cancer. T0901317 and SR1001, two synthetic ligands, have been found to be ROR and ROR inverse agonists that suppress reporter activity and have been shown to delay onset and clinical severity of multiple sclerosis and other Th17 cell-mediated autoimmune diseases. SR1078 has been discovered as a ROR and ROR agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat obesity and diabetes as well as cancer of the breast, ovaries, and prostate. SR3335 has also been discovered as a ROR inverse agonist.