Target Information
| Target General Information | Top | |||||
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| Target ID |
T11241
(Former ID: TTDI02523)
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| Target Name |
Sphingosine-1-phosphate receptor 3 (S1PR3)
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| Synonyms |
Sphingosine 1-phosphate receptor Edg-3; S1PR3; S1P3; S1P receptor Edg-3; S1P receptor 3; Endothelial differentiation G-protein coupled receptor 3
Click to Show/Hide
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| Gene Name |
S1PR3
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| Function |
Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MATALPPRLQPVRGNETLREHYQYVGKLAGRLKEASEGSTLTTVLFLVICSFIVLENLMV
LIAIWKNNKFHNRMYFFIGNLALCDLLAGIAYKVNILMSGKKTFSLSPTVWFLREGSMFV ALGASTCSLLAIAIERHLTMIKMRPYDANKRHRVFLLIGMCWLIAFTLGALPILGWNCLH NLPDCSTILPLYSKKYIAFCISIFTAILVTIVILYARIYFLVKSSSRKVANHNNSERSMA LLRTVVIVVSVFIACWSPLFILFLIDVACRVQACPILFKAQWFIVLAVLNSAMNPVIYTL ASKEMRRAFFRLVCNCLVRGRGARASPIQPALDPSRSKSSSSNNSSHSPKVKEDLPHTAP SSCIMDKNAALQNGIFCN 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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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | EDD7H9 | Drug Info | Preclinical | Breast cancer | [2] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Inhibitor | [+] 35 Inhibitor drugs | + | ||||
| 1 | BDBM50080559 | Drug Info | [3] | |||
| 2 | BDBM50080563 | Drug Info | [3] | |||
| 3 | BDBM50080570 | Drug Info | [3] | |||
| 4 | JCXGHZCWAHCYGY-UHFFFAOYSA-N | Drug Info | [4] | |||
| 5 | MHHFJYABEVJNEG-UHFFFAOYSA-N | Drug Info | [4] | |||
| 6 | US10166249, Example 695 | Drug Info | [5] | |||
| 7 | US10179791, Compound 171 | Drug Info | [6] | |||
| 8 | US10179791, Compound 176 | Drug Info | [6] | |||
| 9 | US10179791, Compound 296 | Drug Info | [6] | |||
| 10 | US8524917, 10 | Drug Info | [7] | |||
| 11 | US8524917, 11 | Drug Info | [8] | |||
| 12 | US8524917, 12 | Drug Info | [8] | |||
| 13 | US8524917, 60 | Drug Info | [7] | |||
| 14 | US8563594, 152 | Drug Info | [8] | |||
| 15 | US9181182, 34 | Drug Info | [9] | |||
| 16 | US9181182, 40 | Drug Info | [9] | |||
| 17 | US9181182, 47 | Drug Info | [9] | |||
| 18 | US9187437, 24 | Drug Info | [10] | |||
| 19 | US9187437, 38 | Drug Info | [10] | |||
| 20 | US9187437, 8 | Drug Info | [10] | |||
| 21 | US9216972, 132 | Drug Info | [11] | |||
| 22 | US9216972, 61 | Drug Info | [11] | |||
| 23 | US9216972, 67 | Drug Info | [11] | |||
| 24 | US9216972, 94 | Drug Info | [11] | |||
| 25 | US9522888, 412 | Drug Info | [5] | |||
| 26 | US9522888, 575 | Drug Info | [12] | |||
| 27 | US9522888, 618 | Drug Info | [5] | |||
| 28 | US9522888, 695 | Drug Info | [12] | |||
| 29 | US9617250, Example 1 Example 204 of D1 | Drug Info | [3] | |||
| 30 | US9670220, 33 | Drug Info | [13] | |||
| 31 | US9670220, 76 | Drug Info | [13] | |||
| 32 | US9670220, 77 | Drug Info | [13] | |||
| 33 | US9707205, 40 | Drug Info | [14] | |||
| 34 | YYDJCLCSBYCSCO-UHFFFAOYSA-N | Drug Info | [4] | |||
| 35 | ZNFTXQFGUIKQQE-UHFFFAOYSA-N | Drug Info | [4] | |||
| Agonist | [+] 4 Agonist drugs | + | ||||
| 1 | AFD(R) | Drug Info | [15] | |||
| 2 | AUY954 | Drug Info | [16] | |||
| 3 | FTY720-phosphate | Drug Info | [17] | |||
| 4 | VPC12249 | Drug Info | [16] | |||
| Antagonist | [+] 3 Antagonist drugs | + | ||||
| 1 | VPC03090-P | Drug Info | [18] | |||
| 2 | VPC23019 | Drug Info | [19] | |||
| 3 | VPC44116 | Drug Info | [16] | |||
| 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: Sphingosine-1-phosphate | Ligand Info | |||||
| Structure Description | Cryo-EM structure of S1P-bound Sphingosine 1-phosphate receptor 3 in complex with Gi protein | PDB:7EW3 | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [20] |
| PDB Sequence |
ETLREHYQYV
25 GKLAGRSTLT42 TVLFLVICSF52 IVLENLMVLI62 AIWKNNKFHN72 RMYFFIGNLA 82 LCDLLAGIAY92 KVNILMSGKK102 TFSLSPTVWF112 LREGSMFVAL122 GASTCSLLAI 132 AIERHLTMIK142 MRPYDANKRH152 RVFLLIGMCW162 LIAFTLGALP172 ILGWNCLHNL 182 PDCSTILPLY192 SKKYIAFCIS202 IFTAILVTIV212 ILYARIYFLV222 KSSSRKVANH 232 NNSERSMALL242 RTVVIVVSVF252 IACWSPLFIL262 FLIDVACRVQ272 ACPILFKAQW 282 FIVLAVLNSA292 MNPVIYTLAS302 KEMRRAFFRL312
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TYR22
2.929
LYS27
3.937
ARG31
2.725
ASN95
3.587
SER99
2.733
GLY100
4.954
THR103
3.964
TRP111
4.112
ARG114
3.832
GLU115
2.661
MET118
3.870
PHE119
3.466
LEU122
2.719
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (S)-FTY720P | Ligand Info | |||||
| Structure Description | Cryo-EM structure of pFTY720-bound Sphingosine 1-phosphate receptor 3 in complex with Gi protein | PDB:7EW2 | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [20] |
| PDB Sequence |
ETLREHYQYV
25 GKLAGRSTLT42 TVLFLVICSF52 IVLENLMVLI62 AIWKNNKFHN72 RMYFFIGNLA 82 LCDLLAGIAY92 KVNILMSGKK102 TFSLSPTVWF112 LREGSMFVAL122 GASTCSLLAI 132 AIERHLTMIK142 MRPYDANKRH152 RVFLLIGMCW162 LIAFTLGALP172 ILGWNCLHNL 182 PDCSTILPLY192 SKKYIAFCIS202 IFTAILVTIV212 ILYARIYFLV222 KSSSRKVANH 232 NNSERSMALL242 RTVVIVVSVF252 IACWSPLFIL262 FLIDVACRVQ272 ACPILFKAQW 282 FIVLAVLNSA292 MNPVIYTLAS302 KEMRRAFFRL312
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TYR22
3.296
LYS27
4.580
ARG31
2.576
TYR92
4.956
ASN95
2.651
SER99
2.554
GLY100
4.448
THR103
3.411
TRP111
4.427
ARG114
3.730
GLU115
2.818
MET118
3.067
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| 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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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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| Sphingolipid signaling pathway | hsa04071 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 9.52E-05 |
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| Closeness centrality | 2.28E-01 | Radiality | 1.40E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 6.05E+01 | Topological coefficient | 2.75E-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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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Sphingolipid signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | S1P3 pathway | |||||
| 2 | Sphingosine 1-phosphate (S1P) pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | G alpha (i) signalling events | |||||
| 2 | Lysosphingolipid and LPA receptors | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Signal Transduction of S1P Receptor | |||||
| 2 | Small Ligand GPCRs | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| References | Top | |||||
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| REF 1 | 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: 277). | |||||
| REF 2 | Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov. 2017 Sep;16(9):787-810. | |||||
| REF 3 | Pyridin-4-yl derivatives. US9617250. | |||||
| REF 4 | 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (S1P) receptor for the treatment of multiple sclerosis. US9150519. | |||||
| REF 5 | Substituted bicyclic compounds. US10166249. | |||||
| REF 6 | Spiro-cyclic amine derivatives as S1P modulators. US10179791. | |||||
| REF 7 | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity. US8524917. | |||||
| REF 8 | S1P3 receptor inhibitors for treating pain. US8563594. | |||||
| REF 9 | S1P receptors modulators. US9181182. | |||||
| REF 10 | Substituted oxadiazole compounds. US9187437. | |||||
| REF 11 | Tricyclic heterocyclic compounds. US9216972. | |||||
| REF 12 | Substituted bicyclic compounds. US9522888. | |||||
| REF 13 | Fused heterocyclic derivatives as S1P modulators. US9670220. | |||||
| REF 14 | S1P receptors modulators and their use thereof. US9707205. | |||||
| REF 15 | The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002 Jun 14;277(24):21453-7. | |||||
| REF 16 | Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem. 2007 Jan 15;15(2):663-77. | |||||
| REF 17 | Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther. 2004 May;309(2):758-68. | |||||
| REF 18 | Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther. 2011 Sep;338(3):879-89. | |||||
| REF 19 | Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem. 2005 Mar 18;280(11):9833-41. | |||||
| REF 20 | Structural insights into sphingosine-1-phosphate recognition and ligand selectivity of S1PR3-Gi signaling complexes. Cell Res. 2022 Feb;32(2):218-221. | |||||
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