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Orphan receptor

January 01, 1970

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 edit

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 edit

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 edit

  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.

External links edit

  • "Class A Orphans GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology.
  • "Adhesion Class GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology.
  • "Class C Orphans GPCRs". IUPHAR/BPS Guide to PHARMACOLOGY Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology.

January 01, 1970
orphan, receptor, this, article, needs, updated, reason, given, ligands, partially, identified, along, with, other, discoveries, please, help, update, this, article, reflect, recent, events, newly, available, information, march, 2024, biochemistry, orphan, rec. This article needs to be updated The reason given is Ligands are now partially identified along with a few other new discoveries Please help update this article to reflect recent events or newly available information March 2024 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 1 Examples 2 Discovery 3 References 4 External linksExamples editExamples 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 editHistorically 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 edit 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 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 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 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 Giguere 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 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 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 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 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 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 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 External links edit Class A Orphans GPCRs IUPHAR BPS Guide to PHARMACOLOGY Database University of Edinburgh International Union of Basic and Clinical Pharmacology Adhesion Class GPCRs IUPHAR BPS Guide to PHARMACOLOGY Database University of Edinburgh International Union of Basic and Clinical Pharmacology Class C Orphans GPCRs IUPHAR BPS Guide to PHARMACOLOGY Database University of Edinburgh International Union of Basic and Clinical Pharmacology Retrieved from https en wikipedia org w index php title Orphan receptor amp oldid 1214805830, wikipedia, wiki, book, books, library,

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