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S1P5 receptor

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 279

Nomenclature: S1P5 receptor

Family: Lysophospholipid (S1P) receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 398 19p13.2 S1PR5 sphingosine-1-phosphate receptor 5
Mouse 7 400 9 A3 S1pr5 sphingosine-1-phosphate receptor 5
Rat 7 400 8q13 S1pr5 sphingosine-1-phosphate receptor 5
Previous and Unofficial Names Click here for help
edg8 | NRG-1 | endothelial differentiation G protein-coupled receptor 8 | nerve growth factor-regulated G-protein-coupled receptor 1
Database Links Click here for help
Specialist databases
GPCRdb s1pr5_human (Hs), s1pr5_mouse (Mm), s1pr5_rat (Rn)
Other databases
Alphafold Q9H228 (Hs), Q91X56 (Mm), Q9JKM5 (Rn)
ChEMBL Target CHEMBL2274 (Hs)
DrugBank Target Q9H228 (Hs)
Ensembl Gene ENSG00000180739 (Hs), ENSMUSG00000045087 (Mm), ENSRNOG00000020901 (Rn)
Entrez Gene 53637 (Hs), 94226 (Mm), 60399 (Rn)
Human Protein Atlas ENSG00000180739 (Hs)
KEGG Gene hsa:53637 (Hs), mmu:94226 (Mm), rno:60399 (Rn)
OMIM 605146 (Hs)
Pharos Q9H228 (Hs)
RefSeq Nucleotide NM_030760 (Hs), NM_053190 (Mm), NM_021775 (Rn)
RefSeq Protein NP_110387 (Hs), NP_444420 (Mm), NP_068543 (Rn)
UniProtKB Q9H228 (Hs), Q91X56 (Mm), Q9JKM5 (Rn)
Wikipedia S1PR5 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Cryo-EM structure of siponimod-bound sphingosine 1-phosphate receptor 5 in complex with Gi protein
PDB Id:  7EW1
Ligand:  siponimod
Resolution:  3.4Å
Species:  Human
References:  34
Image of receptor 3D structure from RCSB PDB
Description:  XFEL crystal structure of the human sphingosine 1-phosphate receptor 5 in complex with ONO-5430608
PDB Id:  7YXA
Resolution:  2.2Å
Species:  Human
References:  21
Natural/Endogenous Ligands Click here for help
dihydrosphingosine 1-phosphate
sphingosine 1-phosphate
sphingosylphosphorylcholine
Comments: Sphingosine 1-phosphate exhibits greater potency than sphingosylphosphorylcholine
Potency order of endogenous ligands
sphingosine 1-phosphate > dihydrosphingosine 1-phosphate  [16]

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
sphingosine 1-phosphate Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Rn Agonist 8.7 pKd 16
⤷ pKd 8.7 [16]
VPC03090-P Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 8.6 pKd 19
⤷ pKd 8.6 (Kd 2.3x10-9 M) [19]
siponimod Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 9.0 pEC50 11-12,30
⤷ pEC50 9.0 (EC50 9.8x10-10 M) [11-12,30]
Description: In a GTPγS binding assay
fingolimod-phosphate Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.2 – 9.5 pEC50 3,9,25
⤷ pEC50 8.2 – 9.5 [3,9,25]
AFD(R) Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.0 – 9.7 pEC50 3,26
⤷ pEC50 8.0 – 9.7 [3,26]
VPC03090-P Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 8.6 pEC50 19
⤷ pEC50 8.6 (EC50 2.4x10-9 M) [19]
A-971432 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Agonist 8.2 – 8.4 pEC50 7,14
⤷ pEC50 8.4 (EC50 4.1x10-9 M) [14]
Description: In a forskolin-induced cAMP inhibition assay in S1P5-transfected CHO cells.
pEC50 8.2 (EC50 5.7x10-9 M) [7,14]
Description: In a GTPγS assay using membranes from S1P5-transfected HEK293 cells.
RP-101075 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 8.2 pEC50 28
⤷ pEC50 8.2 (EC50 5.9x10-9 M) [28]
Description: As measured in a GTPγS assay.
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 7.4 – 8.9 pEC50 3,15,25-26
⤷ pEC50 7.4 – 8.9 [3,15,25-26]
ASP4058 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 8.1 pEC50 33
⤷ pEC50 8.1 (EC50 7.5x10-9 M) [33]
Description: In a GTPγS binding assay.
sphingosine 1-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Agonist 7.8 – 7.9 pEC50 15,26
⤷ pEC50 7.8 – 7.9 (EC50 1.6x10-8 M) [15,26]
compound 43 [PMID: 26751273] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 7.8 pEC50 6
⤷ pEC50 7.8 (EC50 1.66x10-8 M) [6]
Description: In an aequorin calcium accumulation assay.
ozanimod Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 7.3 – 8.0 pEC50 24,27
⤷ pEC50 8.0 (EC50 1.1x10-8 M) [27]
Description: In a GTPγS assay.
pEC50 7.3 (EC50 5.52x10-8 M) [24]
etrasimod Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 7.6 pEC50 4
⤷ pEC50 7.6 (EC50 2.44x10-8 M) [4]
Description: In a β-arrestin recruitment assay.
VPC44116 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.5 pEC50 10
⤷ pEC50 7.5 [10]
GSK2018682 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.2 pEC50 32
⤷ pEC50 7.2 (EC50 6.3x10-8 M) [32]
AUY954 Small molecule or natural product Click here for species-specific activity table Mm Agonist 6.5 pEC50 25
⤷ pEC50 6.5 [25]
AUY954 Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.5 pEC50 25
⤷ pEC50 6.5 (EC50 3.4x10-7 M) [25]
fingolimod-phosphate Small molecule or natural product Click here for species-specific activity table Hs Agonist 9.2 pIC50 9
⤷ pIC50 9.2 (IC50 6x10-10 M) [9]
compound 26 [PMID: 16190743] Small molecule or natural product Click here for species-specific activity table Hs Agonist 9.0 pIC50 20
⤷ pIC50 9.0 [20]
ponesimod Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Partial agonist 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.42x10-7 M) [2]
Description: In a radioligand binding assay using membranes from CHO cells expressing human S1P5
fingolimod Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 5.7 pIC50 13
⤷ pIC50 5.7 (IC50 2.1x10-6 M) [13]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 15 [PMID: 33738061] Small molecule or natural product Hs Antagonist 10.0 pIC50 22
⤷ pIC50 10.0 (IC50 1x10-10 M) [22]
Immunopharmacology Comments
In the immune system S1P receptors regulate immune cell trafficking and mitogenesis, are involved in immune-modulation, and suppression of innate immune T cell responses.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
G12/G13 family 		Adenylyl cyclase inhibition
Comments:  Activation of MAPK [23].
References:  16,23
Tissue Distribution Click here for help
CD56dim NK cells
Species:  Human
Technique:  RT-PCR
References:  31
Brain, spleen, peripheral blood leukocytes, placenta, lung, aorta, and fetal spleen
Species:  Human
Technique:  Northern blot
References:  15
Brain, spleen, embryo (day 7 and 17)
Species:  Human
Technique:  Northern blot
References:  15
Spleen, intestine, brain, vas def, testis, adrenal
Species:  Mouse
Technique:  Northern blot, in situ hybridisation
References:  16
Corpus callosum, anterior commissure, fimbria, and white matter of the cerebellum
Species:  Mouse
Technique:  in situ hybridisation
References:  17
Ly6C− monocytes
Species:  Mouse
Technique:  RT-PCR
References:  5
NK cell
Species:  Mouse
Technique:  RT-PCR
References:  31
Brain, spleen
Species:  Rat
Technique:  Northern blot
References:  16
NG2-positive oligodendrocyte progenitor cells
Species:  Rat
Technique:  Immunocytochemistry
References:  29
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Cell survival
Species:  Mouse
Tissue:  Oligodendrocytes
Response measured:  Survival
References:  17
Cell migration
Species:  Mouse
Tissue:  Oligodendrocytes, NK cells, monocytes
Response measured:  Migration
References:  5,17,31
Physiological Consequences of Altering Gene Expression Click here for help
Aberrant NK cell homing during steady-state conditions in knockout mice.
Species:  Mouse
Tissue:  NK cell
Technique:  Gene knockouts
References:  31
Lacking the egress of Ly6C− monocytes from the bone marrow in knockout mice
Species:  Mouse
Tissue:  Peripheral Ly6C− monocytes
Technique:  Gene knockouts
References:  5
Loss of process retraction in knockout pre-oligodendrocytes
Species:  Mouse
Tissue:  Preoligodendrocytes
Technique:  Gene knockouts
References:  17
Egress of NK cells from lymph nodes and bone marrow
Species:  Mouse
Tissue:  NK cells
Technique:  Gene knockouts
References:  18
S1P5 receptor signaling accelerates mitosis.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts
References:  1
Loss of S1P5 attenuates adenine-induced renal damage.
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockout
References:  8
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
S1pr5tm1Club S1pr5tm1Club/S1pr5tm1Club
involves: 129P2/OlaHsd * C57BL/6J		 MGI:2150641  MP:0003690 abnormal glial cell physiology PMID: 15703400 
S1pr5tm1Jch S1pr5tm1Jch/S1pr5tm1Jch
involves: 129P2/OlaHsd * C57BL/6		 MGI:2150641  MP:0008053 abnormal NK cell differentiation PMID: 19808259 

References

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1. Andrieu G, Ledoux A, Branka S, Bocquet M, Gilhodes J, Walzer T, Kasahara K, Inagaki M, Sabbadini RA, Cuvillier O et al.. (2017) Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Sci Signal, 10 (472). [PMID:28351953]

2. Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C et al.. (2010) 2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem, 53 (10): 4198-211. [PMID:20446681]

3. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P et al.. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem, 277 (24): 21453-7. [PMID:11967257]

4. Buzard DJ, Kim SH, Lopez L, Kawasaki A, Zhu X, Moody J, Thoresen L, Calderon I, Ullman B, Han S et al.. (2014) Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. ACS Med Chem Lett, 5 (12): 1313-7. [PMID:25516790]

5. Debien E, Mayol K, Biajoux V, Daussy C, De Aguero MG, Taillardet M, Dagany N, Brinza L, Henry T, Dubois B et al.. (2013) S1PR5 is pivotal for the homeostasis of patrolling monocytes. Eur J Immunol, 43 (6): 1667-75. [PMID:23519784]

6. Demont EH, Bailey JM, Bit RA, Brown JA, Campbell CA, Deeks N, Dowell SJ, Eldred C, Gaskin P, Gray JR et al.. (2016) Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses. J Med Chem, 59 (3): 1003-20. [PMID:26751273]

7. Di Pardo A, Castaldo S, Amico E, Pepe G, Marracino F, Capocci L, Giovannelli A, Madonna M, van Bergeijk J, Buttari F et al.. (2018) Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum Mol Genet, 27 (14): 2490-2501. [PMID:29688337]

8. Eckes T, Patyna S, Koch A, Oftring A, Gauer S, Obermüller N, Schwalm S, Schaefer L, Chun J, Gröne HJ et al.. (2022) Sphingosine 1-Phosphate Receptor 5 (S1P5) Knockout Ameliorates Adenine-Induced Nephropathy. Int J Mol Sci, 23 (7). [PMID:35409312]

9. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J et al.. (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther, 309 (2): 758-68. [PMID:14747617]

10. Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL. (2007) Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem, 15 (2): 663-77. [PMID:17113298]

11. Gates E. (1998) A complement to care. Nurs Times, 94 (9): 55-7. [PMID:9735753]

12. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG et al.. (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol, 167 (5): 1035-47. [PMID:22646698]

13. Hale JJ, Lynch CL, Neway W, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ, Parent SA et al.. (2004) A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists. J Med Chem, 47 (27): 6662-5. [PMID:15615513]

14. Hobson AD, Harris CM, van der Kam EL, Turner SC, Abibi A, Aguirre AL, Bousquet P, Kebede T, Konopacki DB, Gintant G et al.. (2015) Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders. J Med Chem, 58 (23): 9154-70. [PMID:26509640]

15. Im DS, Clemens J, Macdonald TL, Lynch KR. (2001) Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8): structure-activity relationship of sphingosine1-phosphate receptors. Biochemistry, 40 (46): 14053-60. [PMID:11705398]

16. Im DS, Heise CE, Ancellin N, O'Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G et al.. (2000) Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem, 275 (19): 14281-6. [PMID:10799507]

17. Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K et al.. (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci, 25 (6): 1459-69. [PMID:15703400]

18. Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ, Pereira JP, Xu Y, Roots CM, Beilke JN, Banerjee A et al.. (2009) T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J Exp Med, 206 (11): 2469-81. [PMID:19808259]

19. Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR. (2011) Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther, 338 (3): 879-89. [PMID:21632869]

20. Li Z, Chen W, Hale JJ, Lynch CL, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ et al.. (2005) Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3. J Med Chem, 48 (20): 6169-73. [PMID:16190743]

21. Lyapina E, Marin E, Gusach A, Orekhov P, Gerasimov A, Luginina A, Vakhrameev D, Ergasheva M, Kovaleva M, Khusainov G et al.. (2022) Structural basis for receptor selectivity and inverse agonism in S1P5 receptors. Nat Commun, 13 (1): 4736. [PMID:35961984]

22. Ma B, Guckian KM, Liu XG, Yang C, Li B, Scannevin R, Mingueneau M, Drouillard A, Walzer T. (2021) Novel Potent Selective Orally Active S1P5 Receptor Antagonists. ACS Med Chem Lett, 12 (3): 351-355. [PMID:33738061]

23. Malek RL, Toman RE, Edsall LC, Wong S, Chiu J, Letterle CA, Van Brocklyn JR, Milstien S, Spiegel S, Lee NH. (2001) Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors. J Biol Chem, 276 (8): 5692-9. [PMID:11069896]

24. Martinborough E, Boehm MF, Yeager AR, Tamiya J, Huang L, Brahmachary E, Moorjani M, Timony GA, Brooks JL, Peach R et al.. (2011) Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis. Patent number: US20110172202 A1. Assignee: Martinborough E, Boehm MF, Yeager AR, Tamiya J, Huang L, Brahmachary E, Moorjani M, Timony GA, Brooks JL, Peach R et al.. Priority date: 13/11/2009. Publication date: 14/07/2011.

25. Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S et al.. (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol, 13 (11): 1227-34. [PMID:17114004]

26. Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N et al.. (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem, 279 (14): 13839-48. [PMID:14732717]

27. Scott FL, Clemons B, Brooks J, Brahmachary E, Powell R, Dedman H, Desale HG, Timony GA, Martinborough E, Rosen H et al.. (2016) Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br J Pharmacol, 173 (11): 1778-92. [PMID:26990079]

28. Taylor Meadows KR, Steinberg MW, Clemons B, Stokes ME, Opiteck GJ, Peach R, Scott FL. (2018) Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PLoS ONE, 13 (4): e0193236. [PMID:29608575]

29. Terai K, Soga T, Takahashi M, Kamohara M, Ohno K, Yatsugi S, Okada M, Yamaguchi T. (2003) Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience, 116 (4): 1053-62. [PMID:12617946]

30. Urbano M, Guerrero M, Rosen H, Roberts E. (2013) Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg Med Chem Lett, 23 (23): 6377-89. [PMID:24125884]

31. Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E. (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol, 8 (12): 1337-44. [PMID:17965716]

32. Xu J, Gray F, Henderson A, Hicks K, Yang J, Thompson P, Oliver J. (2014) Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers. Clin Pharmacol Drug Dev, 3 (3): 170-8. [PMID:27128606]

33. Yamamoto R, Okada Y, Hirose J, Koshika T, Kawato Y, Maeda M, Saito R, Hattori K, Harada H, Nagasaka Y et al.. (2014) ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS ONE, 9 (10): e110819. [PMID:25347187]

34. Yuan Y, Jia G, Wu C, Wang W, Cheng L, Li Q, Li Z, Luo K, Yang S, Yan W et al.. (2021) Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Cell Res, 31 (12): 1263-1274. [PMID:34526663]

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