Target Information
| Target General Information | Top | |||||
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| Target ID |
T10491
(Former ID: TTDI02326)
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| Target Name |
C-X-C chemokine receptor type 7 (ACKR3)
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| Synonyms |
RDC1; RDC-1; Gprotein coupled receptor RDC1 homolog; Gprotein coupled receptor 159; GPR159; G-protein coupled receptor RDC1 homolog; G-protein coupled receptor 159; Chemokine orphan receptor 1; CXCR7; CXCR-7; CXC-R7; CXC chemokine receptor type 7; CMKOR1; Atypical chemokine receptor 3
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| Gene Name |
ACKR3
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| Target Type |
Preclinical target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Asthma [ICD-11: CA23] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1. Chemokine binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization and activation of MAPK signaling pathway. Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and enhanced cell adhesion and migration. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Acts as coreceptor with CXCR4 for a restricted number of HIV isolates. Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMI
ANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVT HLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDT YYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAIS ASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVT QCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQS TK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | GW-766994 | Drug Info | Discontinued in Phase 2 | Asthma | [2], [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | GW-766994 | Drug Info | [1] | |||
| 2 | CCX-662 | Drug Info | [5] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Cryo-EM structure of ACKR3 in complex with chemokine N-terminal mutant CXCL12_LRHQ, an intracellular Fab, and an extracellular Fab | PDB:7SK4 | ||||
| Method | Electron microscopy | Resolution | 3.30 Å | Mutation | Yes | [6] |
| PDB Sequence |
IVVDTVMCPN
36 MPNKSVLLYT46 LSFIYIFIFV56 IGMIANSVVV66 WVNIQAKTTG76 YDTHCYILNL 86 AIADLWVVLT96 IPVWVVSLVQ106 HNQWPMGELT116 CKVTHLIFSI126 NLFGSIFFLT 136 CMSVDRYLSI146 TYFTNTPSSR156 KKMVRRVVCI166 LVWLLAFCVS176 LPDTYYLKTV 186 TSASNNETYC196 RSFYPEHSIK206 EWLIGMELVS216 VVLGFAVPFS226 IIAVFYFLLA 236 RAISASSDQE246 KHSSRKIIFS256 YVVVFLVCWL266 PYHVAVLLDI276 FSILHYIPFT 286 CRLEHALFTA296 LHVTQCLSLV306 HCCVNPVLYS316 FINRNYRYEL326 MKAFI |
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CYS81
4.663
TYR82
4.655
LEU84
3.394
ASN85
2.776
ILE88
2.397
TRP92
2.904
LEU122
3.649
ILE123
2.884
ILE126
2.619
ASN127
2.580
ILE132
4.746
PHE133
2.474
THR136
2.618
CYS137
2.530
VAL140
2.844
LEU144
2.554
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydroxypiperidin-1-yl)-1,3-thiazol-4-yl]methyl}-1,4-diazepan-1-ium | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human ACKR3 in complex with CXCL12, a small molecule partial agonist CCX662, and an extracellular Fab | PDB:7SK7 | ||||
| Method | Electron microscopy | Resolution | 3.30 Å | Mutation | No | [6] |
| PDB Sequence |
CIVVDTVMCP
35 NMPNKSVLLY45 TLSFIYIFIF55 VIGMIANSVV65 VWVNIQHCYI83 LNLAIADLWV 93 VLTIPVWVVS103 LVQHNQWPMG113 ELTCKVTHLI123 FSINLFGSIF133 FLTCMSVDRY 143 LSITYRKKMV160 RRVVCILVWL170 LAFCVSLPDT180 YYLKTVTSAS190 NNETYCRSFY 200 PEHSIKEWLI210 GMELVSVVLG220 FAVPFSIIAV230 FYFLLARSRK252 IIFSYVVVFL 262 VCWLPYHVAV272 LLDIFSILHY282 IPFTCRLEHA292 LFTALHVTQC302 LSLVHCCVNP 312 VLYSFIN
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TYR51
2.597
ILE97
4.109
TRP100
2.710
SER103
2.764
LEU104
3.256
ASN108
2.583
TRP110
4.039
HIS121
2.175
PHE124
2.221
SER125
2.422
LEU128
2.217
PHE129
3.006
ILE132
2.450
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
|---|---|---|---|
| Olfactory receptor 4C11 (OR4C11) | 26.772 (34/127) | 4.00E-03 | |
| Olfactory receptor 10G4 (OR10G4) | 29.060 (34/117) | 4.00E-03 |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cytokine-cytokine receptor interaction | hsa04060 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Viral protein interaction with cytokine and cytokine receptor | hsa04061 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 5.76E-05 |
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| Closeness centrality | 2.08E-01 | Radiality | 1.36E+01 | Clustering coefficient | 4.00E-01 |
| Neighborhood connectivity | 2.26E+01 | Topological coefficient | 2.73E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Cytokine-cytokine receptor interaction | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | TNFalpha Signaling Pathway | |||||
| 2 | TGF_beta_Receptor Signaling Pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Chemokine receptors bind chemokines | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Myometrial Relaxation and Contraction Pathways | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| References | Top | |||||
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| REF 1 | Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2014 Apr;44(4):508-16. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3530). | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019095) | |||||
| REF 4 | Clinical pipeline report, company report or official report of Jyant Technologies. | |||||
| REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 80). | |||||
| REF 6 | Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. Sci Adv. 2022 Jul 15;8(28):eabn8063. | |||||
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