Biology:Orphan receptor
In biochemistry, an orphan receptor is a protein that is structurally similar to a receptor, but for which no physiological relevant endogenous ligand is known. If a biologically significant ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".[1] Conversely, the term orphan ligand refers to a biological ligand whose cognate receptor has not yet been identified. Because it can take time for terminology in common use to change, and disagreements can exist about whether a discovered endogenous ligand has a biologically significant function, specific adopted orphans may continue to be referred to as orphans for some time after their ligand is found, despite no longer being true orphans.
Examples
Examples of orphan receptors are found in the G protein-coupled receptor (GPCR)[2][3][4] and nuclear receptor[5][6][7] families.
If an endogenous ligand is found, the orphan receptor is "adopted" or "de-orphanized".[7] An example is the nuclear receptor farnesoid X receptor (FXR) and TGR5/GPCR19/G protein-coupled bile acid receptor, both of which are activated by bile acids.[8] Adopted orphan receptors in the nuclear receptor group include FXR, liver X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR). Another example of an orphan receptor site is the PCP binding site in the NMDA receptor,[9] a type of ligand-gated ion channel. This site is where the recreational drug PCP works, but no endogenous ligand is known to bind to this site.
GPCR orphan receptors are usually given the name "GPR" followed by a number, for example GPR21. In the GPCR family, nearly 100 receptor-like genes remain orphans.[10]
Discovery
Historically, receptors were discovered by using ligands to "fish" for their receptors. Hence, by definition, these receptors were not orphans. However, with modern molecular biology techniques such as reverse pharmacology, screening of cDNA libraries, and whole genome sequencing, receptors have been identified based on sequence similarity to known receptors, without knowing what their ligands are.
References
- ↑ "ONRLDB--manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery". Database 2015. 2015. doi:10.1093/database/bav112. PMID 26637529.
- ↑ "Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers". EMBO Reports 7 (11): 1094–1098. 2006. doi:10.1038/sj.embor.7400838. PMID 17077864.
- ↑ "Orphan GPCRs and their ligands". Pharmacology & Therapeutics 110 (3): 525–532. 2006. doi:10.1016/j.pharmthera.2005.10.001. PMID 16289308.
- ↑ "The identification of ligands at orphan G-protein coupled receptors". Annual Review of Pharmacology and Toxicology 44 (February): 43–66. 2004. doi:10.1146/annurev.pharmtox.44.101802.121419. PMID 14744238.
- ↑ "Orphan nuclear receptors: from gene to function". Endocrine Reviews 20 (5): 689–725. October 1999. doi:10.1210/edrv.20.5.0378. PMID 10529899.
- ↑ "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacological Reviews 58 (4): 798–836. 2006. doi:10.1124/pr.58.4.10. PMID 17132856.
- ↑ 7.0 7.1 "Orphan nuclear receptors in drug discovery". Drug Discovery Today 12 (11–12): 440–445. June 2007. doi:10.1016/j.drudis.2007.04.006. PMID 17532527.
- ↑ "Structural basis for bile acid binding and activation of the nuclear receptor FXR". Molecular Cell 11 (4): 1093–1100. April 2003. doi:10.1016/S1097-2765(03)00112-6. PMID 12718893.
- ↑ "Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes". Neuroscience Letters 76 (2): 221–227. May 1987. doi:10.1016/0304-3940(87)90719-1. PMID 2438606.
- ↑ "The G protein-coupled receptors deorphanization landscape". Biochemical Pharmacology 153: 62–74. July 2018. doi:10.1016/j.bcp.2018.02.016. PMID 29454621.
External links
- "Class A Orphans GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=16.
- "Adhesion Class GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=17.
- "Class C Orphans GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=18.
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