Target Information

Target General Information

Target ID

T50089 (Former ID: TTDI02167)

Target Name

Sphingosine-1-phosphate receptor 5 (S1PR5)

Synonyms

Sphingosine 1-phosphate receptor Edg-8; S1PR5; S1P5; S1P receptor Edg-8; S1P receptor 5; Endothelial differentiation G-protein-coupled receptor 8

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Gene Name

S1PR5

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Multiple sclerosis [ICD-11: 8A40]

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. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins. May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells.

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BioChemical Class

GPCR rhodopsin

UniProt ID

S1PR5_HUMAN

Sequence

MESGLLRPAPVSEVIVLHYNYTGKLRGARYQPGAGLRADAVVCLAVCAFIVLENLAVLLV
LGRHPRFHAPMFLLLGSLTLSDLLAGAAYAANILLSGPLTLKLSPALWFAREGGVFVALT
ASVLSLLAIALERSLTMARRGPAPVSSRGRTLAMAAAAWGVSLLLGLLPALGWNCLGRLD
ACSTVLPLYAKAYVLFCVLAFVGILAAICALYARIYCQVRANARRLPARPGTAGTTSTRA
RRKPRSLALLRTLSVVLLAFVACWGPLFLLLLLDVACPARTCPVLLQADPFLGLAMANSL
LNPIIYTLTNRDLRHALLRLVCCGRHSCGRDPSGSQQSASAAEASGGLRRCLPPGLDGSF
SGSERSSPQRDGLDTSGSTGSPGAPTAARTLVSEPAAD

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ASP-4058

Drug Info

Phase 1

Multiple sclerosis

[1]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 1 Modulator drugs

ASP-4058

Drug Info

[1]

Agonist

[+] 5 Agonist drugs

AFD(R)

Drug Info

[2]

AUY954

Drug Info

[3]

FTY720-phosphate

Drug Info

[4]

VPC03090-P

Drug Info

[5]

VPC44116

Drug Info

[6]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid

Ligand Info

Structure Description

Cryo-EM structure of siponimod -bound Sphingosine-1-phosphate receptor 5 in complex with Gi protein

PDB:7EW1

Method

Electron microscopy

Resolution

3.40 Å

Mutation

[7]

PDB Sequence

VIVLHYNYTG

²³

KLRGRADAVV

⁴²

CLAVCAFIVL

⁵²

ENLAVLLVLG

⁶²

RHAPMFLLLG

⁷⁶

SLTLSDLLAG

⁸⁶

AAYAANILLS

⁹⁶

GPLTLKLSPA

¹⁰⁶

LWFAREGGVF

¹¹⁶

VALTASVLSL

¹²⁶

LAIALERSLT

¹³⁶

MARRGPAPVS

¹⁴⁶

SRGRTLAMAA

¹⁵⁶

AAWGVSLLLG

¹⁶⁶

LLPALGWNCL

¹⁷⁶

GRLDACSTVL

¹⁸⁶

PLYAKAYVLF

¹⁹⁶

CVLAFVGILA

²⁰⁶

AICALYARIY

²¹⁶

CQVRANARRL

²²⁶

RKPRSLALLR

²⁵¹

TLSVVLLAFV

²⁶¹

ACWGPLFLLL

²⁷¹

LLDVACPART

²⁸¹

CPVLLQADPF

²⁹¹

LGLAMANSLL

³⁰¹

NPIIYTLTN

Residue

Distance (Å)

TYR19

4.606

LYS24

2.578

ASN92

2.927

SER96

4.424

LEU101

4.845

TRP108

3.451

ARG111

4.129

GLU112

3.310

VAL115

4.032

PHE116

3.839

LEU119

3.590

THR120

3.196

VAL123

3.662

Residue

Distance (Å)

LEU124

4.581

VAL185

4.740

LEU186

4.025

CYS197

2.521

VAL198

4.261

ALA200

4.590

PHE201

4.055

TRP264

3.970

LEU267

2.769

LEU271

4.271

ALA288

3.665

LEU292

3.786

Ligand Name: 4-[6-(2-naphthalen-1-ylethoxy)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-ium-3-yl]butanoic acid

Ligand Info

Structure Description

XFEL crystal structure of the human sphingosine 1 phosphate receptor 5 in complex with ONO-5430608

PDB:7YXA

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

Yes

[8]

PDB Sequence

LRPAPVSEVI

¹⁵

VLHYNYTGKL

²⁵

RGARYQPGAG

³⁵

LRADAVVCLA

⁴⁵

VCAFIVLENL

⁵⁵

AVLLVLGRHP

⁶⁵

RFHAPMFLLL

⁷⁵

GSLTLSDLLA

⁸⁵

GAAYAANILL

⁹⁵

SGPLTLKLSP

¹⁰⁵

ALWFAREGGV

¹¹⁵

FVALTASVLS

¹²⁵

LLAIALERSL

¹³⁵

TSRGRTLAMA

¹⁵⁵

AAAWGVSLLL

¹⁶⁵

GLLPALGWNC

¹⁷⁵

LGRLDACSTV

¹⁸⁵

LPLYAKAYVL

¹⁹⁵

FCVLAFVGIL

²⁰⁵

AAICALYARI

²¹⁵

YCQVRANAAD

¹⁰⁰²

LEDNWETLND

¹⁰¹²

NLKVIEKADN

¹⁰²²

AAQVKDALTK

¹⁰³²

MRAAALDAQK

¹⁰⁴²

AEMKDFRHGF

¹⁰⁶⁵

DILVGQIDDA

¹⁰⁷⁵

LKLANEGKVK

¹⁰⁸⁵

EAQAAAEQLK

¹⁰⁹⁵

TTRNARSLAL

²⁴⁹

LRTLSVVLLA

²⁵⁹

FVACWGPLFL

²⁶⁹

LLLLDVACPA

²⁷⁹

RTCPVLLQAD

²⁸⁹

PFLGLAMANS

²⁹⁹

LLNPIIYTLT

³⁰⁹

NRDLRHALLR

³¹⁹

LVGRP

Residue

Distance (Å)

TYR19

1.543

LYS24

2.680

ARG37

3.690

CYS43

3.774

TYR89

3.079

ASN92

2.688

ILE93

2.775

SER96

4.884

THR100

4.539

TRP108

3.012

ARG111

1.782

GLU112

2.026

VAL115

2.625

Residue

Distance (Å)

PHE116

3.828

VAL185

2.452

LEU186

2.257

PRO187

2.534

TRP264

3.380

LEU267

2.302

ASP289

2.235

PRO290

4.463

PHE291

4.971

LEU292

2.197

GLY293

2.179

ALA295

2.490

MET296

2.517

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Different Human System Profiles of Target	Top
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 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 Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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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 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 Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 4K3 (OR4K3)	PF13853	22.603 (66/292)	3.89E-05
Olfactory receptor 4D10 (OR4D10)	PF13853	24.832 (74/298)	9.63E-05
Olfactory receptor 4D9 (OR4D9)	PF13853	24.749 (74/299)	1.04E-04
Olfactory receptor 5AC1 (OR5AC1)	PF13853	23.692 (77/325)	1.21E-04
Olfactory receptor 4K5 (OR4K5)	PF13853	24.324 (72/296)	2.44E-04
Olfactory receptor 4D11 (OR4D11)	PF13853	24.483 (71/290)	2.45E-04
Olfactory receptor 11L1 (OR11L1)	PF13853	22.981 (74/322)	3.07E-04
Olfactory receptor 11A1 (OR11A1)	PF13853	23.323 (73/313)	2.00E-03
Olfactory receptor 4C46 (OR4C46)	PF13853	33.333 (34/102)	4.00E-03
Olfactory receptor 10S1 (OR10S1)	PF13853	45.455 (15/33)	5.00E-03
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KEGG Pathway	Pathway ID	Affiliated Target
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	3.15E-07
Closeness centrality	1.79E-01	Radiality	1.29E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.45E+01	Topological coefficient	5.40E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Sphingolipid signaling pathway

Neuroactive ligand-receptor interaction

PID Pathway

[+] 3 PID Pathways

S1P4 pathway

S1P5 pathway

Sphingosine 1-phosphate (S1P) pathway

Reactome

[+] 2 Reactome Pathways

G alpha (i) signalling events

Lysosphingolipid and LPA receptors

WikiPathways

[+] 3 WikiPathways

Signal Transduction of S1P Receptor

GPCR ligand binding

GPCR downstream signaling

References

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REF 1

ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS One. 2014 Oct 27;9(10):e110819.

REF 2

Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004 Apr 2;279(14):13839-48.

REF 3

A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol. 2006 Nov;13(11):1227-34.

REF 4

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 5

Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther. 2011 Sep;338(3):879-89.

REF 6

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 7

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Cell Res. 2021 Dec;31(12):1263-1274.

REF 8

Structural basis for receptor selectivity and inverse agonism in S1P(5) receptors. Nat Commun. 2022 Aug 12;13(1):4736.

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