Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T13852 Target Info
Target Name Sphingosine-1-phosphate receptor 1 (S1PR1)
Synonyms Sphingosine 1-phosphate receptor Edg-1; S1P1; S1P receptor Edg-1; S1P receptor 1; Endothelial differentiation G-protein coupled receptor 1; CHEDG1; CD363
Target Type Successful Target
Gene Name S1PR1
Biochemical Class GPCR rhodopsin
UniProt ID
S1PR1_HUMAN
Ligand General Information  Top
Ligand Name 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid Ligand Info
Canonical SMILES CCC1=C(C=CC(=C1)C(=NOCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)C)CN4CC(C4)C(=O)O
InChI 1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)
InChIKey KIHYPELVXPAIDH-UHFFFAOYSA-N
PubChem Compound ID 72959169
Drug Binding Sites of Target  Top
PDB ID: 7EO4      Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312
Method Electron microscopy Resolution 2.86 Å Mutation No [1]
PDB Sequence
SDYVNYDIIV
26
RHYNYTGKLN
36
IKLTSVVFIL
54
ICCFIILENI
64
FVLLTIWKTK
74

KFHRPMYYFI
84
GNLALSDLLA
94
GVAYTANLLL
104
SGATTYKLTP
114
AQWFLREGSM
124

FVALSASVWS
134
LLAIAIERYI
144
TMLKMKNFRL
160
FLLISACWVI
170
SLILGGLPIM
180

GWNCISALSS
190
CSTVLPLYHK
200
HYILFCTTVF
210
TLLLLSIVIL
220
YCRIYSLVRT
230

RSRRLTFRSL
252
ALLKTVIIVL
262
SVFIACWAPL
272
FILLLLDVGC
282
KVKTCDILFR
292

AEYFLVLAVL
302
NSGTNPIIYT
312
LTNKEMRRAF
322
IR
Residue
Distance (Å)
TYR29
4.858
ASN101
3.120
SER105
3.046
GLY106
3.160
THR109
4.294
ARG120
3.567
GLU121
4.162
MET124
3.436
PHE125
3.368
LEU128
3.375
SER129
3.077
VAL132
3.809
TRP133
4.127
VAL194
3.858
Residue
Distance (Å)
LEU195
4.225
ILE203
4.944
CYS206
2.742
THR207
3.498
VAL209
3.457
PHE210
3.526
LEU213
4.887
TRP269
4.475
LEU272
4.245
PHE273
4.911
LEU276
3.282
ALA293
3.375
GLU294
4.565
LEU297
4.314
PDB ID: 7TD4      Sphingosine-1-phosphate receptor 1-Gi complex bound to Siponimod
Method Electron microscopy Resolution 2.60 Å Mutation Yes [2]
PDB Sequence
DYVNYDIIVR
27
HYNYTGKLNI
45
KLTSVVFILI
55
CCFIILENIF
65
VLLTIWKTKK
75

FHRPMYYFIG
85
NLALSDLLAG
95
VAYTANLLLS
105
GATTYKLTPA
115
QWFLREGSMF
125

VALSASVFSL
135
LAIAIERYIT
145
MLKMKLHNGS
155
NNFRLFLLIS
165
ACWVISLILG
175

GLPIMGWNCI
185
SALSSCSTVL
195
PLYHKHYILF
205
CTTVFTLLLL
215
SIVILYCRIY
225

SLVRTRSRRL
235
TFRKSEKSLA
253
LLKTVIIVLS
263
VFIACWAPLF
273
ILLLLDVGCK
283

VKTCDILFRA
293
EYFLVLAVLN
303
SGTNPIIYTL
313
TNKEMRRAFI
323
Residue
Distance (Å)
TYR29
3.622
LYS34
3.508
ASN101
3.273
SER105
3.348
GLY106
4.038
THR109
2.935
ARG120
3.227
GLU121
3.446
MET124
4.089
PHE125
3.568
LEU128
3.540
SER129
3.483
VAL132
3.906
PHE133
4.222
Residue
Distance (Å)
LEU174
3.817
VAL194
3.780
LEU195
3.486
CYS206
2.993
THR207
3.591
VAL209
3.610
PHE210
3.597
LEU213
3.681
TRP269
3.834
LEU272
4.325
LEU276
2.838
ALA293
4.225
GLU294
3.965
LEU297
3.628
PDB ID: 7EVY      Cryo-EM structure of siponimod -bound Sphingosine-1-phosphate receptor 1 in complex with Gi protein
Method Electron microscopy Resolution 2.98 Å Mutation No [3]
PDB Sequence
YDIIVRHYNY
31
TGKLTSVVFI
53
LICCFIILEN
63
IFVLLTIWKT
73
KKFHRPMYYF
83

IGNLALSDLL
93
AGVAYTANLL
103
LSGATTYKLT
113
PAQWFLREGS
123
MFVALSASVF
133

SLLAIAIERY
143
ITMLKMKLHN
153
GSNNFRLFLL
163
ISACWVISLI
173
LGGLPIMGWN
183

CISALSSCST
193
VLPLYHKHYI
203
LFCTTVFTLL
213
LLSIVILYCR
223
IYSLVRTRSR
233

RLTFRKNISE
249
KSLALLKTVI
259
IVLSVFIACW
269
APLFILLLLD
279
VGCKVKTCDI
289

LFRAEYFLVL
299
AVLNSGTNPI
309
IYTLTNKEMR
319
RAFIRI
Residue
Distance (Å)
TYR29
2.289
LYS34
2.460
ASN101
4.383
SER105
4.602
THR109
4.853
TRP117
3.980
ARG120
4.230
GLU121
3.297
MET124
3.550
PHE125
3.019
LEU128
3.617
SER129
2.798
VAL132
4.134
PHE133
4.812
Residue
Distance (Å)
VAL194
3.557
LEU195
4.070
CYS206
3.192
THR207
3.573
VAL209
3.769
PHE210
3.672
LEU213
4.443
TRP269
4.429
LEU272
3.544
PHE273
4.756
LEU276
2.164
ALA293
3.175
GLU294
4.402
LEU297
3.688
References  Top
REF 1 Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. Nat Chem Biol. 2022 Mar;18(3):281-288.
REF 2 Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun. 2022 Feb 8;13(1):731.
REF 3 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.

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