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{{Short description|A protein with a receptor structure but with unidentified ligand}}
{{Short description|A protein with a receptor structure but with unidentified ligand}}
In [[biochemistry]], an '''orphan receptor''' is a protein that has a similar structure to other identified [[receptor (biochemistry)|receptors]] but whose [[endogenous]] [[ligand (biochemistry)|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".<ref name="Nanduri2015">{{Cite journal|last=Nanduri|first=Ravikanth|last2=Bhutani|first2=Isha|last3=Somavarapu|first3=Arun Kumar|last4=Mahajan|first4=Sahil|last5=Parkesh|first5=Raman|last6=Gupta|first6=Pawan|date=2015-01-01|title=ONRLDB—manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery|url=https://academic.oup.com/database/article/doi/10.1093/database/bav112/2433243|journal=Database|language=en|volume=2015|doi=10.1093/database/bav112|pmc=4669993}}</ref> Conversely, the term '''orphan ligand''' refers to a biological ligand whose cognate receptor has not yet been identified.
In [[biochemistry]], an '''orphan receptor''' is a protein that has a similar structure to other identified [[receptor (biochemistry)|receptors]] but whose [[endogenous]] [[ligand (biochemistry)|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".<ref name="Nanduri2015">{{Cite journal|last=Nanduri|first=Ravikanth|last2=Bhutani|first2=Isha|last3=Somavarapu|first3=Arun Kumar|last4=Mahajan|first4=Sahil|last5=Parkesh|first5=Raman|last6=Gupta|first6=Pawan|date=2015-01-01|title=ONRLDB—manually curated database of experimentally validated ligands for orphan nuclear receptors: insights into new drug discovery|journal=Database|language=en|volume=2015|pages=bav112|doi=10.1093/database/bav112|pmid=26637529|pmc=4669993}}</ref> Conversely, the term '''orphan ligand''' refers to a biological ligand whose cognate receptor has not yet been identified.


==Examples==
==Examples==
Examples of orphan receptors are found in the [[G protein-coupled receptor]] (GPCR)<ref name="Levoye_2006">{{cite journal |vauthors=Levoye A, Dam J, Ayoub MA, Guillaume JL, Jockers R |title=Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers|journal= EMBO Rep |volume= 7 |issue= 11 |pages= 1094–8 |year= 2006| doi = 10.1038/sj.embor.7400838 |pmid= 17077864 |pmc=1679777}}</ref><ref name="Civelli_2006">{{cite journal |vauthors=Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK |title=Orphan GPCRs and their ligands|journal= Pharmacol Ther |volume= 110 |issue= 3 |pages= 525–32 |year= 2006| doi = 10.1016/j.pharmthera.2005.10.001 |pmid= 16289308}}</ref><ref name="Wise_2004">{{cite journal |vauthors=Wise A, Jupe SC, Rees S |title=The identification of ligands at orphan G-protein coupled receptors|journal= Annu Rev Pharmacol Toxicol |volume= 44 |issue= February |pages= 43–66 |year= 2004| doi = 10.1146/annurev.pharmtox.44.101802.121419 |pmid= 14744238}}</ref> and [[nuclear receptor]]<ref name="pmid10529899">{{cite journal | author = Giguère V | title = Orphan nuclear receptors: from gene to function | journal = Endocr. Rev. | volume = 20 | issue = 5 | pages = 689–725 |date=October 1999 | pmid = 10529899 | doi = 10.1210/er.20.5.689 | url = }}</ref><ref name="Benoit_2006">{{cite journal |vauthors=Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V |title=International Union of Pharmacology. LXVI. Orphan nuclear receptors|journal= Pharmacol Rev |volume= 58 |issue= 4 |pages= 798–836 |year= 2006| doi = 10.1124/pr.58.4.10 |pmid= 17132856}}</ref><ref name="pmid17532527">{{cite journal | author = Shi Y | title = Orphan Nuclear Receptors in Drug Discovery | journal = Drug Discov. Today | volume = 12 | issue = 11–12 | pages = 440–5 |date=June 2007 | pmid = 17532527 | doi = 10.1016/j.drudis.2007.04.006 | url = | pmc = 2748783 }}</ref> families.
Examples of orphan receptors are found in the [[G protein-coupled receptor]] (GPCR)<ref name="Levoye_2006">{{cite journal |vauthors=Levoye A, Dam J, Ayoub MA, Guillaume JL, Jockers R |title=Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers|journal= EMBO Rep |volume= 7 |issue= 11 |pages= 1094–8 |year= 2006| doi = 10.1038/sj.embor.7400838 |pmid= 17077864 |pmc=1679777}}</ref><ref name="Civelli_2006">{{cite journal |vauthors=Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK |title=Orphan GPCRs and their ligands|journal= Pharmacol Ther |volume= 110 |issue= 3 |pages= 525–32 |year= 2006| doi = 10.1016/j.pharmthera.2005.10.001 |pmid= 16289308}}</ref><ref name="Wise_2004">{{cite journal |vauthors=Wise A, Jupe SC, Rees S |title=The identification of ligands at orphan G-protein coupled receptors|journal= Annu Rev Pharmacol Toxicol |volume= 44 |issue= February |pages= 43–66 |year= 2004| doi = 10.1146/annurev.pharmtox.44.101802.121419 |pmid= 14744238|url=https://semanticscholar.org/paper/2667289ead0c043e4fead2b2e6b69b8e6da5003c}}</ref> and [[nuclear receptor]]<ref name="pmid10529899">{{cite journal | author = Giguère V | title = Orphan nuclear receptors: from gene to function | journal = Endocr. Rev. | volume = 20 | issue = 5 | pages = 689–725 |date=October 1999 | pmid = 10529899 | doi = 10.1210/er.20.5.689 | url = }}</ref><ref name="Benoit_2006">{{cite journal |vauthors=Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V |title=International Union of Pharmacology. LXVI. Orphan nuclear receptors|journal= Pharmacol Rev |volume= 58 |issue= 4 |pages= 798–836 |year= 2006| doi = 10.1124/pr.58.4.10 |pmid= 17132856|url=https://semanticscholar.org/paper/145c9ca61ad30494d76a80998308368a1e08a68e}}</ref><ref name="pmid17532527">{{cite journal | author = Shi Y | title = Orphan Nuclear Receptors in Drug Discovery | journal = Drug Discov. Today | volume = 12 | issue = 11–12 | pages = 440–5 |date=June 2007 | pmid = 17532527 | doi = 10.1016/j.drudis.2007.04.006 | url = | pmc = 2748783 }}</ref> families.


If an endogenous ligand is found, the orphan receptor is "adopted" or "de-orphanized"<ref>{{Cite journal|last=SHI|first=Y|title=Orphan nuclear receptors in drug discovery|url=|journal=Drug Discovery Today|volume=12|issue=11-12|pages=440–445|doi=10.1016/j.drudis.2007.04.006|pmc=2748783}}</ref>. An example is the nuclear receptor [[Farnesoid X receptor|Farnesoid X receptor (FXR)]] and the GPCR [[G protein-coupled bile acid receptor|TGR5/GPCR19/G protein-coupled bile acid receptor]], both of which are activated by [[bile acid]]s.<ref name="pmid12718893">{{cite journal |vauthors=Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F | title = Structural basis for bile acid binding and activation of the nuclear receptor FXR | journal = Mol. Cell | volume = 11 | issue = 4 | pages = 1093–100 |date=April 2003 | pmid = 12718893 | doi = 10.1016/S1097-2765(03)00112-6| url = }}</ref> 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 [[phencyclidine|PCP]] binding site in the [[NMDA receptor]],<ref name="pmid2438606">{{cite journal | author = Fagg GE | title = Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes | journal = Neurosci. Lett. | volume = 76 | issue = 2 | pages = 221–7 |date=May 1987 | pmid = 2438606 | doi = 10.1016/0304-3940(87)90719-1| url = }}</ref> 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.
If an endogenous ligand is found, the orphan receptor is "adopted" or "de-orphanized"<ref>{{Cite journal|last=SHI|first=Y|title=Orphan nuclear receptors in drug discovery|url=|journal=Drug Discovery Today|volume=12|issue=11–12|pages=440–445|doi=10.1016/j.drudis.2007.04.006|pmid=17532527|pmc=2748783|year=2007}}</ref>. An example is the nuclear receptor [[Farnesoid X receptor|Farnesoid X receptor (FXR)]] and the GPCR [[G protein-coupled bile acid receptor|TGR5/GPCR19/G protein-coupled bile acid receptor]], both of which are activated by [[bile acid]]s.<ref name="pmid12718893">{{cite journal |vauthors=Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F | title = Structural basis for bile acid binding and activation of the nuclear receptor FXR | journal = Mol. Cell | volume = 11 | issue = 4 | pages = 1093–100 |date=April 2003 | pmid = 12718893 | doi = 10.1016/S1097-2765(03)00112-6| url = }}</ref> 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 [[phencyclidine|PCP]] binding site in the [[NMDA receptor]],<ref name="pmid2438606">{{cite journal | author = Fagg GE | title = Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes | journal = Neurosci. Lett. | volume = 76 | issue = 2 | pages = 221–7 |date=May 1987 | pmid = 2438606 | doi = 10.1016/0304-3940(87)90719-1| url = }}</ref> 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.<ref name=”pmid29454621”>{{cite journal |last1=Laschet |first1=C |last2=Dupuis |first2=N |last3=Hanson |first3=J |date=2018 |title=The G protein-coupled receptors deorphanization landscape |url= |journal=Biochemical Pharmacology |volume=153 |issue= |pages=62-74 |doi=10.1016/j.bcp.2018.02.016 |access-date= }}</ref>
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.<ref name=”pmid29454621”>{{cite journal |last1=Laschet |first1=C |last2=Dupuis |first2=N |last3=Hanson |first3=J |date=2018 |title=The G protein-coupled receptors deorphanization landscape |url= |journal=Biochemical Pharmacology |volume=153 |issue= |pages=62–74 |doi=10.1016/j.bcp.2018.02.016 |pmid=29454621 |access-date= }}</ref>


==Discovery==
==Discovery==

Revision as of 12:53, 1 December 2019

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 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.
  5. ^ Giguère V (October 1999). "Orphan nuclear receptors: from gene to function". Endocr. Rev. 20 (5): 689–725. doi:10.1210/er.20.5.689. 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.
  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.
  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.
  • "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.
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