Orphan receptor

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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.

Contents

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 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 GPR21. 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

  1. ↑ 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". Database. 2015: bav112. doi:10.1093/database/bav112. PMC   4669993 . PMID   26637529.
  2. ↑ Levoye A, Dam J, Ayoub MA, Guillaume JL, Jockers R (2006). "Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers". EMBO Rep. 7 (11): 1094–8. doi:10.1038/sj.embor.7400838. PMC   1679777 . PMID   17077864.
  3. ↑ Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK (2006). "Orphan GPCRs and their ligands". Pharmacol Ther. 110 (3): 525–32. doi:10.1016/j.pharmthera.2005.10.001. PMID   16289308.
  4. ↑ Wise A, Jupe SC, Rees S (2004). "The identification of ligands at orphan G-protein coupled receptors". Annu Rev Pharmacol Toxicol. 44 (February): 43–66. doi:10.1146/annurev.pharmtox.44.101802.121419. PMID   14744238. S2CID   2618257.
  5. ↑ 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.
  6. ↑ 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. doi:10.1124/pr.58.4.10. PMID   17132856. S2CID   2619263.
  7. ↑ 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. PMC   2748783 . PMID   17532527.
  8. ↑ 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. PMC   2748783 . PMID   17532527.
  9. ↑ Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F (April 2003). "Structural basis for bile acid binding and activation of the nuclear receptor FXR". Mol. Cell. 11 (4): 1093–100. doi: 10.1016/S1097-2765(03)00112-6 . PMID   12718893.
  10. ↑ 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. S2CID   23177400.
  11. ↑ 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. S2CID   3566341.
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