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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 362 | 2q37.3 | ACKR3 | atypical chemokine receptor 3 | |
| Mouse | 7 | 362 | 1 45.28 cM | Ackr3 | atypical chemokine receptor 3 | |
| Rat | 7 | 362 | 9q36 | Ackr3 | atypical chemokine receptor 3 | |
| Previous and Unofficial Names |
| chemokine (C-X-C motif) receptor 7 | chemokine orphan receptor 1 | CXCR7 | Cxcr7 | GPR159 | G-protein coupled receptor 159 | G-protein coupled receptor RDC1 homolog | RDC-1 |
| Database Links |
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| Specialist databases | |
| GPCRdb | ackr3_human (Hs), ackr3_mouse (Mm), ackr3_rat (Rn) |
| Other databases | |
| Alphafold | P25106 (Hs), P56485 (Mm), O89039 (Rn) |
| ChEMBL Target | CHEMBL2010631 (Hs), CHEMBL4105796 (Mm), CHEMBL4739671 (Rn) |
| Ensembl Gene | ENSG00000144476 (Hs), ENSMUSG00000044337 (Mm), ENSRNOG00000019622 (Rn) |
| Entrez Gene | 57007 (Hs), 12778 (Mm), 84348 (Rn) |
| Human Protein Atlas | ENSG00000144476 (Hs) |
| KEGG Gene | hsa:57007 (Hs), mmu:12778 (Mm), rno:84348 (Rn) |
| OMIM | 610376 (Hs) |
| Pharos | P25106 (Hs) |
| RefSeq Nucleotide | NM_020311 (Hs), NM_007722 (Mm), NM_053352 (Rn) |
| RefSeq Protein | NP_064707 (Hs), NP_031748 (Mm), NP_445804 (Rn) |
| UniProtKB | P25106 (Hs), P56485 (Mm), O89039 (Rn) |
| Wikipedia | ACKR3 (Hs) |
| Natural/Endogenous Ligands |
| adrenomedullin {Sp: Rat} |
| CXCL11 {Sp: Human} |
| CXCL12α {Sp: Human} |
| Comments: Several lines of evidence have suggested that adrenomedullin is a ligand for ACKR3; however, classical direct binding to the receptor has not yet been convincingly demonstrated. |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Burns et al. show that CXCL12 (SDF-1α) binding of CXCR7 is inhibited by CXCL11 (I-TAC) [3]. CXCR7 is demonstrated to bind to CXCL1 with high affinity. The agonist activity of CXCL12 at CXCR7 has been confirmed [1]. A selective small molecule agonist, CCX771 (chemical structure unavailable) binds hACKR3 with an IC50 of 4.1nM [19]. |
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| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| Immunopharmacology Comments |
| ACKR3 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. ACKR3 binds the chemokine CXCL12 (stromal cell-derived factor 1, SDF-1 which is also a ligand for CXCR4). ACKR3 is an atypical receptor in that it does not activate G-protein-mediated signaling but induces β-arrestin recruitment [8], and in heterodimers with CXCR4, regulates CXCL12-mediated G protein signaling [11]. The ACKR3/CXCL12 axis is involved in physiological (developmental and regenerative) and pathological (regulation of cell growth, survival, adhesion, and invasion of many types of cancers and cytokine-driven angiogenesis) processes . |
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| Tissue Distribution
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| Expression Datasets |
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Gene Expression and Pathophysiology
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| General Comments |
| ACKR3 signals exclusively through β-arrestin-mediated pathways and does not activate canonical G protein signalling [6]. It appears to act predominantly as a regulator of the chemokine network in developmental, homeostatic and infalmmatory processes, and in infection and cancer [15]. CXCL11 and CXCL12 are ligands for ACKR3. Expression of ACKR3 is upregulated in some types of cancer making it a potential molecular target for drug development [12,18]. |
1. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 280 (42): 35760-6. [PMID:16107333]
2. Berahovich RD, Zabel BA, Penfold ME, Lewén S, Wang Y, Miao Z, Gan L, Pereda J, Dias J, Slukvin II, McGrath KE, Jaen JC, Schall TJ. (2010) CXCR7 Protein Is Not Expressed on Human or Mouse Leukocytes. J Immunol, 185 (9): 5130-9. [PMID:20889540]
3. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ. (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 203 (9): 2201-13. [PMID:16940167]
4. Gerrits H, van Ingen Schenau DS, Bakker NE, van Disseldorp AJ, Strik A, Hermens LS, Koenen TB, Krajnc-Franken MA, Gossen JA. (2008) Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Genesis, 46 (5): 235-45. [PMID:18442043]
5. Gravel S, Malouf C, Boulais PE, Berchiche YA, Oishi S, Fujii N, Leduc R, Sinnett D, Heveker N. (2010) The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem, 285 (49): 37939-43. [PMID:20956518]
6. Gustavsson M, Wang L, van Gils N, Stephens BS, Zhang P, Schall TJ, Yang S, Abagyan R, Chance MR, Kufareva I et al.. (2017) Structural basis of ligand interaction with atypical chemokine receptor 3. Nat Commun, 8: 14135. [PMID:28098154]
7. Humpert ML, Tzouros M, Thelen S, Bignon A, Levoye A, Arenzana-Seisdedos F, Balabanian K, Bachelerie F, Langen H, Thelen M. (2012) Complementary methods provide evidence for the expression of CXCR7 on human B cells. Proteomics, 12 (12): 1938-48. [PMID:22623068]
8. Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N. (2009) AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol, 75 (5): 1240-7. [PMID:19255243]
9. Kapas S, Clark AJ. (1995) Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor. Biochem Biophys Res Commun, 217 (3): 832-8. [PMID:8554605]
10. Klein KR, Karpinich NO, Espenschied ST, Willcockson HH, Dunworth WP, Hoopes SL, Kushner EJ, Bautch VL, Caron KM. (2014) Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev Cell, 30 (5): 528-40. [PMID:25203207]
11. Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B. (2009) CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood, 113 (24): 6085-93. [PMID:19380869]
12. Melo RCC, Longhini AL, Bigarella CL, Baratti MO, Traina F, Favaro P, de Melo Campos P, Saad ST. (2014) CXCR7 is highly expressed in acute lymphoblastic leukemia and potentiates CXCR4 response to CXCL12. PLoS ONE, 9 (1): e85926. [PMID:24497931]
13. Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, Simon K, Ohnmacht J, Turner JD, Krüger R et al.. (2020) The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nat Commun, 11 (1): 3033. [PMID:32561830]
14. Neusser MA, Kraus AK, Regele H, Cohen CD, Fehr T, Kerjaschki D, Wüthrich RP, Penfold ME, Schall T, Segerer S. (2010) The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection. Kidney Int, 77 (9): 801-8. [PMID:20164826]
15. Nibbs RJ, Graham GJ. (2013) Immune regulation by atypical chemokine receptors. Nat Rev Immunol, 13 (11): 815-29. [PMID:24319779]
16. Sierro F, Biben C, Martínez-Muñoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martínez-A C, Mackay CR, Mackay F. (2007) Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA, 104 (37): 14759-64. [PMID:17804806]
17. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]
18. Wurth R, Tarn K, Jernigan D, Fernandez SV, Cristofanilli M, Fatatis A, Meucci O. (2015) A Preclinical Model of Inflammatory Breast Cancer to Study the Involvement of CXCR4 and ACKR3 in the Metastatic Process. Transl Oncol, 8 (5): 358-67. [PMID:26500026]
19. Zabel BA, Wang Y, Lewén S, Berahovich RD, Penfold ME, Zhang P, Powers J, Summers BC, Miao Z, Zhao B, Jalili A, Janowska-Wieczorek A, Jaen JC, Schall TJ. (2009) Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol, 183 (5): 3204-11. [PMID:19641136]
target has curated data in GtoImmuPdb
