Biology:Orphan receptor
In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a 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.
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".[8] An example is the nuclear receptor farnesoid X receptor (FXR) and the GPCR TGR5/GPCR19/G protein-coupled bile acid receptor, both of which are activated by bile acids.[9] 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,[10] 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 GPR1. In the GPCR family, nearly 100 receptor-like genes remain orphans.[11]
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
- ↑ Nanduri, Ravikanth; Bhutani, Isha; Somavarapu, Arun Kumar; Mahajan, Sahil; Parkesh, Raman; Gupta, Pawan (2015-01-01). "ONRLDB—manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery" (in en). Database 2015: bav112. doi:10.1093/database/bav112. PMID 26637529.
- ↑ "Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers". EMBO Rep 7 (11): 1094–8. 2006. doi:10.1038/sj.embor.7400838. PMID 17077864.
- ↑ "Orphan GPCRs and their ligands". Pharmacol Ther 110 (3): 525–32. 2006. doi:10.1016/j.pharmthera.2005.10.001. PMID 16289308.
- ↑ "The identification of ligands at orphan G-protein coupled receptors". Annu Rev Pharmacol Toxicol 44 (February): 43–66. 2004. doi:10.1146/annurev.pharmtox.44.101802.121419. PMID 14744238.
- ↑ Giguère V (October 1999). "Orphan nuclear receptors: from gene to function". Endocr. Rev. 20 (5): 689–725. doi:10.1210/edrv.20.5.0378. PMID 10529899.
- ↑ "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacol Rev 58 (4): 798–836. 2006. doi:10.1124/pr.58.4.10. PMID 17132856.
- ↑ Shi Y (June 2007). "Orphan Nuclear Receptors in Drug Discovery". Drug Discov. Today 12 (11–12): 440–5. doi:10.1016/j.drudis.2007.04.006. PMID 17532527.
- ↑ SHI, Y (2007). "Orphan nuclear receptors in drug discovery". Drug Discovery Today 12 (11–12): 440–445. doi:10.1016/j.drudis.2007.04.006. PMID 17532527.
- ↑ "Structural basis for bile acid binding and activation of the nuclear receptor FXR". Mol. Cell 11 (4): 1093–100. April 2003. doi:10.1016/S1097-2765(03)00112-6. PMID 12718893.
- ↑ Fagg GE (May 1987). "Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes". Neurosci. Lett. 76 (2): 221–7. doi:10.1016/0304-3940(87)90719-1. PMID 2438606.
- ↑ Laschet, C; Dupuis, N; Hanson, J (2018). "The G protein-coupled receptors deorphanization landscape". Biochemical Pharmacology 153: 62–74. 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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