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==Ligands==
==Ligands==
Several selective antagonists for the PAR1 receptor have been developed, for use as anti-clotting agents for the treatment of heart disease.


=== Antagonist ===
* [[SCH-530,348]]
⚫
Selective antagonists for the PAR1 receptor have been developed for use as anti-clotting agents. [[Vorapaxar]], sold under the brand name Zontivity<sup>(TM)</sup>, is a first-in-class anti-platelet drug used in the treatment of heart disease in patients with a history of [[Myocardial infarction|heart attacks]] and [[peripheral artery disease]].<ref>{{Cite journal|last=Gryka|first=Rebecca J.|last2=Buckley|first2=Leo F.|last3=Anderson|first3=Sarah M.|date=2017-3|title=Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease|url=http://link.springer.com/10.1007/s40268-016-0158-4|journal=Drugs in R&D|language=en|volume=17|issue=1|pages=65–72|doi=10.1007/s40268-016-0158-4|issn=1174-5886|pmc=PMC5318326|pmid=28063023}}</ref> Vorapaxar has been recently shown to attenuate the [[neutrophilic]] inflammatory response to ''[[Streptococcus pneumoniae]]'' by reducing levels of pro-inflamamtory [[cytokine]]s such as [[IL-1β]] and [[chemokine]]s [[CXCL1]], [[CCL2]] and [[CCL7]].<ref name="PMID25948816">{{cite journal | vauthors = José RJ, Williams AE, Mercer PF, Sulikowski MG, Brown JS, Chambers RC | title = Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection | journal = Journal of Immunology | volume = 194 | issue = 12 | pages = 6024–34 | date = Jun 2015 | pmid = 25948816 | doi = 10.4049/jimmunol.1500124 | pmc=4456635}}</ref>


PAR1 is inhibited by Vorapaxar when the molecule binds to a binding pocket between extracellular loop 2 and 3 of the PAR1 where it stabilizes the inactivated protein structure and prevents the switch to the active conformation.<ref name=":4">{{Cite journal|last=Zhang|first=Cheng|last2=Srinivasan|first2=Yoga|last3=Arlow|first3=Daniel H.|last4=Fung|first4=Juan Jose|last5=Palmer|first5=Daniel|last6=Zheng|first6=Yaowu|last7=Green|first7=Hillary F.|last8=Pandey|first8=Anjali|last9=Dror|first9=Ron O.|date=2012-12-20|title=High-resolution crystal structure of human Protease-Activated Receptor 1 bound to the antagonist vorapaxar|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531875/|journal=Nature|volume=492|issue=7429|pages=387–392|doi=10.1038/nature11701|issn=0028-0836|pmc=PMCPMC3531875|pmid=23222541}}</ref>
⚫
SCH530348 has been recently shown to attenuate the [[neutrophilic]] inflammatory response to ''[[Streptococcus pneumoniae]]'' by reducing levels of pro-inflamamtory [[cytokine]]s such as [[IL-1β]] and [[chemokine]]s [[CXCL1]], [[CCL2]] and [[CCL7]].<ref name="PMID25948816">{{cite journal | vauthors = José RJ, Williams AE, Mercer PF, Sulikowski MG, Brown JS, Chambers RC | title = Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection | journal = Journal of Immunology | volume = 194 | issue = 12 | pages = 6024–34 | date = Jun 2015 | pmid = 25948816 | doi = 10.4049/jimmunol.1500124 | pmc=4456635}}</ref>

=== Agonist ===
Finding selective agonists for PAR1 has also been a topic of interest for researchers. A synthetic SFLLRN peptide has been found to serve as an agonist for PAR1. The SFLLRN peptide mimics the first six residues of the N-terminal tethered ligand of activated PAR1 and binds to the same binding site on the second extracellular loop.<ref name=":4" /> So, even in the absence of thrombin, SFLLRN binding can garner a response from cleaved or uncleaved PAR1.<ref>{{Cite journal|last=Hammes|first=Stephen R.|last2=Coughlin|first2=Shaun R.|date=1999-02|title=Protease-Activated Receptor-1 Can Mediate Responses to SFLLRN in Thrombin-Desensitized Cells:  Evidence for a Novel Mechanism for Preventing or Terminating Signaling by PAR1's Tethered Ligand†|url=http://dx.doi.org/10.1021/bi982527i|journal=Biochemistry|volume=38|issue=8|pages=2486–2493|doi=10.1021/bi982527i|issn=0006-2960}}</ref>


== See also ==
== See also ==

Revision as of 03:55, 13 June 2019

"F2R" redirects here. For the Navy fighter, see Ryan XF2R Dark Shark.
F2R
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesF2R, CHTR, PAR-1, PAR1, TR, Coagulation factor II receptor, coagulation factor II thrombin receptor
External IDsOMIM: 187930; MGI: 101802; HomoloGene: 1510; GeneCards: F2R; OMA:F2R - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2149

14062

Ensembl

ENSG00000181104

ENSMUSG00000048376

UniProt

P25116

P30558

RefSeq (mRNA)

NM_001992
NM_001311313

NM_010169

RefSeq (protein)

NP_001298242
NP_001983

NP_034299

Location (UCSC)Chr 5: 76.72 – 76.74 MbChr 13: 95.74 – 95.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Proteinase-activated receptor 1 (PAR1) also known as Protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene.[5] PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases.[6] It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.[7]

Structure

PAR1 is a transmembrane G-protein-coupled receptor (GPCR) that shares much of its structure with the other protease-actived receptors[8][9]. These characteristics include having seven transmembrane alpha helices, four extracellular loops and three intracellular loops.[9] PAR1 specifically contains 425 amino acid residues arranged for optimal binding of thrombin at its extracellular N-terminus. The C-terminus of PAR1 is located on the intracellular side of the cell membrane as part of its cytoplasmic tail.[8]


Signal Transduction Pathway

This image gives an overview of the cleavage of PAR1 by thrombin. Thrombin, in red, binds to the cleavage site at the extracellular N-terminus of PAR1. Thrombin cleaves the peptide bond between Arg-41 and Ser-42 to reveal a tethered ligand at the new N-terminus and the cleaved peptide, in orange, is released outside of the cell.

Activation

PAR1 is activated when the terminal 41 amino acids of its N-terminus are cleaved by thrombin, a serine protease[10]. Thrombin recognizes PAR1 by a Lysine-Aspartate-Proline-Arginine-Serine sequence at the N-terminal where it cuts the peptide bond between Arginine-41 and Serine-42. The affinity of thrombin to this specific cleavage site in PAR1 is further aided by secondary interactions between thrombin’s exosite and an acidic region of amino acid residues located C-terminal to Ser-42.[11] This proteolytic cleavage is irreversible and the loose peptide, often referred to as parstatin, is then released outside of the cell.[10] The newly revealed N-terminus acts as a tethered ligand that binds to a binding region between extracellular loops 3 and 4 of PAR1, therefore activating the protein. The binding instigates conformation changes in the protein that ultimately allow for the binding of G-proteins to sites on the intracellular region of PAR1.[12]

Ligands

Antagonist

Selective antagonists for the PAR1 receptor have been developed for use as anti-clotting agents. Vorapaxar, sold under the brand name Zontivity(TM), is a first-in-class anti-platelet drug used in the treatment of heart disease in patients with a history of heart attacks and peripheral artery disease.[13] Vorapaxar has been recently shown to attenuate the neutrophilic inflammatory response to Streptococcus pneumoniae by reducing levels of pro-inflamamtory cytokines such as IL-1β and chemokines CXCL1, CCL2 and CCL7.[14]

PAR1 is inhibited by Vorapaxar when the molecule binds to a binding pocket between extracellular loop 2 and 3 of the PAR1 where it stabilizes the inactivated protein structure and prevents the switch to the active conformation.[15]

Agonist

Finding selective agonists for PAR1 has also been a topic of interest for researchers. A synthetic SFLLRN peptide has been found to serve as an agonist for PAR1. The SFLLRN peptide mimics the first six residues of the N-terminal tethered ligand of activated PAR1 and binds to the same binding site on the second extracellular loop.[15] So, even in the absence of thrombin, SFLLRN binding can garner a response from cleaved or uncleaved PAR1.[16]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000181104 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048376 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Bahou WF, Nierman WC, Durkin AS, Potter CL, Demetrick DJ (Sep 1993). "Chromosomal assignment of the human thrombin receptor gene: localization to region q13 of chromosome 5". Blood. 82 (5): 1532–7. PMID 8395910.
  6. ^ "José RJ, Williams AE, Chambers RC (Feb 2014). "Proteinase-activated receptors in fibroproliferative lung disease". Thorax. 69 (2): 190–2. doi:10.1136/thoraxjnl-2013-204367. PMID 24186921.
  7. ^ Feistritzer C, Riewald M (Apr 2005). "Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1–phosphate receptor-1 crossactivation". blood. 105 (8): 3178–84. doi:10.1182/blood-2004-10-3985. PMID 15626732.
  8. ^ a b Platelets. Michelson, Alan D. (3rd ed ed.). Amsterdam: Elsevier. 2013. ISBN 9780123878380. OCLC 820818942. {{cite book}}: |edition= has extra text (help)CS1 maint: others (link)
  9. ^ a b Spoerri, Patrizia M.; Kato, Hideaki E.; Pfreundschuh, Moritz; Mari, Stefania A.; Serdiuk, Tetiana; Thoma, Johannes; Sapra, K. Tanuj; Zhang, Cheng; Kobilka, Brian K. (2018-06). "Structural Properties of the Human Protease-Activated Receptor 1 Changing by a Strong Antagonist". Structure. 26 (6): 829–838.e4. doi:10.1016/j.str.2018.03.020. ISSN 0969-2126. {{cite journal}}: Check date values in: |date= (help)
  10. ^ a b Soh, Unice JK; Dores, Michael R; Chen, Buxin; Trejo, JoAnn (2010-5). "Signal transduction by protease-activated receptors". British Journal of Pharmacology. 160 (2): 191–203. doi:10.1111/j.1476-5381.2010.00705.x. ISSN 0007-1188. PMC 2874842. PMID 20423334. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  11. ^ Arora, P.; Ricks, T. K.; Trejo, J. (2007-02-27). "Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer". Journal of Cell Science. 120 (6): 921–928. doi:10.1242/jcs.03409. ISSN 0021-9533.
  12. ^ Pfreundschuh, Moritz; Alsteens, David; Wieneke, Ralph; Zhang, Cheng; Coughlin, Shaun R.; Tampé, Robert; Kobilka, Brian K.; Müller, Daniel J. (2015-11-12). "Identifying and quantifying two ligand-binding sites while imaging native human membrane receptors by AFM". Nature Communications. 6 (1). doi:10.1038/ncomms9857. ISSN 2041-1723.
  13. ^ Gryka, Rebecca J.; Buckley, Leo F.; Anderson, Sarah M. (2017-3). "Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease". Drugs in R&D. 17 (1): 65–72. doi:10.1007/s40268-016-0158-4. ISSN 1174-5886. PMC 5318326. PMID 28063023. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  14. ^ José RJ, Williams AE, Mercer PF, Sulikowski MG, Brown JS, Chambers RC (Jun 2015). "Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection". Journal of Immunology. 194 (12): 6024–34. doi:10.4049/jimmunol.1500124. PMC 4456635. PMID 25948816.
  15. ^ a b Zhang, Cheng; Srinivasan, Yoga; Arlow, Daniel H.; Fung, Juan Jose; Palmer, Daniel; Zheng, Yaowu; Green, Hillary F.; Pandey, Anjali; Dror, Ron O. (2012-12-20). "High-resolution crystal structure of human Protease-Activated Receptor 1 bound to the antagonist vorapaxar". Nature. 492 (7429): 387–392. doi:10.1038/nature11701. ISSN 0028-0836. PMC PMCPMC3531875. PMID 23222541. {{cite journal}}: Check |pmc= value (help)
  16. ^ Hammes, Stephen R.; Coughlin, Shaun R. (1999-02). "Protease-Activated Receptor-1 Can Mediate Responses to SFLLRN in Thrombin-Desensitized Cells:  Evidence for a Novel Mechanism for Preventing or Terminating Signaling by PAR1's Tethered Ligand†". Biochemistry. 38 (8): 2486–2493. doi:10.1021/bi982527i. ISSN 0006-2960. {{cite journal}}: Check date values in: |date= (help); no-break space character in |title= at position 94 (help)

Further reading

  • Coughlin SR, Vu TK, Hung DT, Wheaton VI (Feb 1992). "Characterization of a functional thrombin receptor. Issues and opportunities". The Journal of Clinical Investigation. 89 (2): 351–5. doi:10.1172/JCI115592. PMC 442859. PMID 1310691.
  • Wu H, Zhang Z, Li Y, Zhao R, Li H, Song Y, Qi J, Wang J (Oct 2010). "Time course of upregulation of inflammatory mediators in the hemorrhagic brain in rats: correlation with brain edema". Neurochemistry International. 57 (3): 248–53. doi:10.1016/j.neuint.2010.06.002. PMC 2910823. PMID 20541575.
  • Howell DC, Laurent GJ, Chambers RC (Apr 2002). "Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis". Biochemical Society Transactions. 30 (2): 211–6. doi:10.1042/BST0300211. PMID 12023853.
  • Tellez C, Bar-Eli M (May 2003). "Role and regulation of the thrombin receptor (PAR-1) in human melanoma". Oncogene. 22 (20): 3130–7. doi:10.1038/sj.onc.1206453. PMID 12789289.
  • Remillard CV, Yuan JX (May 2005). "PGE2 and PAR-1 in pulmonary fibrosis: a case of biting the hand that feeds you?". American Journal of Physiology. Lung Cellular and Molecular Physiology. 288 (5): L789-92. doi:10.1152/ajplung.00016.2005. PMID 15821019.
  • Leger AJ, Covic L, Kuliopulos A (Sep 2006). "Protease-activated receptors in cardiovascular diseases". Circulation. 114 (10): 1070–7. doi:10.1161/CIRCULATIONAHA.105.574830. PMID 16952995.
  • Traynelis SF, Trejo J (May 2007). "Protease-activated receptor signaling: new roles and regulatory mechanisms". Current Opinion in Hematology. 14 (3): 230–5. doi:10.1097/MOH.0b013e3280dce568. PMID 17414212.
  • Vu TK, Hung DT, Wheaton VI, Coughlin SR (Mar 1991). "Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation". Cell. 64 (6): 1057–68. doi:10.1016/0092-8674(91)90261-V. PMID 1672265.
  • Wojtukiewicz MZ, Tang DG, Ben-Josef E, Renaud C, Walz DA, Honn KV (Feb 1995). "Solid tumor cells express functional "tethered ligand" thrombin receptor". Cancer Research. 55 (3): 698–704. PMID 7834643.
  • Hein L, Ishii K, Coughlin SR, Kobilka BK (Nov 1994). "Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitization of a G protein-coupled receptor". The Journal of Biological Chemistry. 269 (44): 27719–26. PMID 7961693.
  • Mathews II, Padmanabhan KP, Ganesh V, Tulinsky A, Ishii M, Chen J, Turck CW, Coughlin SR, Fenton JW (Mar 1994). "Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes". Biochemistry. 33 (11): 3266–79. doi:10.1021/bi00177a018. PMID 8136362.
  • Offermanns S, Laugwitz KL, Spicher K, Schultz G (Jan 1994). "G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 91 (2): 504–8. doi:10.1073/pnas.91.2.504. PMC 42977. PMID 8290554.
  • Hoffman M, Church FC (Aug 1993). "Response of blood leukocytes to thrombin receptor peptides". Journal of Leukocyte Biology. 54 (2): 145–51. PMID 8395550.
  • Schmidt VA, Vitale E, Bahou WF (Apr 1996). "Genomic cloning and characterization of the human thrombin receptor gene. Structural similarity to the proteinase activated receptor-2 gene". The Journal of Biological Chemistry. 271 (16): 9307–12. doi:10.1074/jbc.271.16.9809. PMID 8621593.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Li F, Baykal D, Horaist C, Yan CN, Carr BN, Rao GN, Runge MS (Oct 1996). "Cloning and identification of regulatory sequences of the human thrombin receptor gene". The Journal of Biological Chemistry. 271 (42): 26320–8. doi:10.1074/jbc.271.42.26320. PMID 8824285.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Shapiro MJ, Trejo J, Zeng D, Coughlin SR (Dec 1996). "Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization". The Journal of Biological Chemistry. 271 (51): 32874–80. doi:10.1074/jbc.271.51.32874. PMID 8955127.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Ogino Y, Tanaka K, Shimizu N (Nov 1996). "Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells". European Journal of Pharmacology. 316 (1): 105–9. doi:10.1016/S0014-2999(96)00653-X. PMID 8982657.
  • Molino M, Bainton DF, Hoxie JA, Coughlin SR, Brass LF (Feb 1997). "Thrombin receptors on human platelets. Initial localization and subsequent redistribution during platelet activation". The Journal of Biological Chemistry. 272 (9): 6011–7. doi:10.1074/jbc.272.9.6011. PMID 9038223.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Renesto P, Si-Tahar M, Moniatte M, Balloy V, Van Dorsselaer A, Pidard D, Chignard M (Mar 1997). "Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor". Blood. 89 (6): 1944–53. PMID 9058715.

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