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 T02562 Target Info
Target Name Prostaglandin E synthase (PTGES)
Synonyms p53-induced gene 12 protein; PIG12; PGES; PGE synthase; P53-induced apoptosis protein 12; Microsomal prostaglandin E synthase 1; Microsomal glutathione S-transferase 1-like 1; MPGES1; MPGES-1; MGST1L1; MGST1-L1
Target Type Clinical trial Target
Gene Name PTGES
Biochemical Class Intramolecular oxidoreductase
UniProt ID
PTGES_HUMAN
Ligand General Information  Top
Ligand Name Glutathione Ligand Info
Canonical SMILES C(CC(=O)NC(CS)C(=O)NCC(=O)O)C(C(=O)O)N
InChI 1S/C10H17N3O6S/c11-5(10(18)19)1-2-7(14)13-6(4-20)9(17)12-3-8(15)16/h5-6,20H,1-4,11H2,(H,12,17)(H,13,14)(H,15,16)(H,18,19)/t5-,6-/m0/s1
InChIKey RWSXRVCMGQZWBV-WDSKDSINSA-N
PubChem Compound ID 124886
Drug Binding Sites of Target  Top
PDB ID: 4AL0      Crystal structure of Human PS-1
Method X-ray diffraction Resolution 1.16 Å Mutation No [1]
PDB Sequence
VMSSPALPAF
16
LLCSTLLVIK
26
MYVVAIITGQ
36
VRLRKKAFAN
46
PEDALRHGGP
56

QYCRSDPDVE
66
RCLRAHRNDM
76
ETIYPFLFLG
86
FVYSFLGPNP
96
FVAWMHFLVF
106

LVGRVAHTVA
116
YLGKLRAPIR
126
SVTYTLAQLP
136
CASMALQILW
146
EAARHL
Residue
Distance (Å)
ARG70
3.630
ARG73
2.886
ASN74
2.878
GLU77
2.914
HIS113
2.872
Residue
Distance (Å)
TYR117
2.592
ARG126
2.887
SER127
3.056
TYR130
3.173
PDB ID: 5TL9      crystal structure of mPGES-1 bound to inhibitor
Method X-ray diffraction Resolution 1.20 Å Mutation No [2]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYRSDPDV
65
ERCLRAHRND
75
METIYPFLFL
85
GFVYSFLGPN
95
PFVAWMHFLV
105

FLVGRVAHTV
115
AYLGKLRAPI
125
RSVTYTLAQL
135
PCASMALQIL
145
WEAARHL
Residue
Distance (Å)
ARG70
3.569
ARG73
2.890
ASN74
2.934
GLU77
2.827
HIS113
2.898
Residue
Distance (Å)
TYR117
2.595
ARG126
2.876
SER127
3.071
TYR130
3.156
PDB ID: 5K0I      mpges1 bound to an inhibitor
Method X-ray diffraction Resolution 1.30 Å Mutation No [3]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYRSDPDV
65
ERCLRAHRND
75
METIYPFLFL
85
GFVYSFLGPN
95
PFVAWMHFLV
105

FLVGRVAHTV
115
AYLGKLRAPI
125
RSVTYTLAQL
135
PCASMALQIL
145
WEAARHL
Residue
Distance (Å)
ARG70
3.590
ASN74
2.922
GLU77
2.860
HIS113
2.849
Residue
Distance (Å)
TYR117
2.595
ARG126
2.838
SER127
3.091
TYR130
3.153
PDB ID: 5T36      Crystal structure of mPGES-1 bound to inhibitor
Method X-ray diffraction Resolution 1.40 Å Mutation No [2]
PDB Sequence
LVMSSPALPA
15
FLLCSTLLVI
25
KMYVVAIITG
35
QVRLRKKAFA
45
NPEDALRHGG
55

PQYCRSDPDV
65
ERCLRAHRND
75
METIYPFLFL
85
GFVYSFLGPN
95
PFVAWMHFLV
105

FLVGRVAHTV
115
AYLGKLRAPI
125
RSVTYTLAQL
135
PCASMALQIL
145
WEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.568
ARG73
4.947
ASN74
2.871
GLU77
2.904
HIS113
2.780
Residue
Distance (Å)
TYR117
2.597
ARG126
2.797
SER127
3.024
TYR130
3.170
PDB ID: 4YK5      Crystal Structures of mPGES-1 Inhibitor Complexes
Method X-ray diffraction Resolution 1.42 Å Mutation No [4]
PDB Sequence
VMSSPALPAF
16
LLCSTLLVIK
26
MYVVAIITGQ
36
VRLRKKAFAN
46
PEDALRHGGP
56

QYCRSDPDVE
66
RCLRAHRNDM
76
ETIYPFLFLG
86
FVYSFLGPNP
96
FVAWMHFLVF
106

LVGRVAHTVA
116
YLGKLRAPIR
126
SVTYTLAQLP
136
CASMALQILW
146
EAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.611
ASN74
2.862
GLU77
2.822
HIS113
2.884
Residue
Distance (Å)
TYR117
2.598
ARG126
2.891
SER127
3.031
TYR130
3.180
PDB ID: 5BQG      Crystal Structure of mPGES-1 Bound to an Inhibitor
Method X-ray diffraction Resolution 1.44 Å Mutation No [5]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYCRSDPD
64
VERCLRAHRN
74
DMETIYPFLF
84
LGFVYSFLGP
94
NPFVAWMHFL
104

VFLVGRVAHT
114
VAYLGKLRAP
124
IRSVTYTLAQ
134
LPCASMALQI
144
LWEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.654
ARG73
2.881
ASN74
2.896
GLU77
2.831
HIS113
2.893
Residue
Distance (Å)
TYR117
2.605
ARG126
2.873
SER127
3.102
TYR130
3.163
PDB ID: 5BQH      Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain
Method X-ray diffraction Resolution 1.60 Å Mutation No [5]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYCRSDPD
64
VERCLRAHRN
74
DMETIYPFLF
84
LGFVYSFLGP
94
NPFVAWMHFL
104

VFLVGRVAHT
114
VAYLGKLRAP
124
IRSVTYTLAQ
134
LPCASMALQI
144
LWEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.604
ASN74
2.951
GLU77
3.036
HIS113
2.851
Residue
Distance (Å)
TYR117
2.577
ARG126
2.912
SER127
3.271
TYR130
3.226
PDB ID: 5T37      crystal structure of mPGES-1 bound to inhibitor
Method X-ray diffraction Resolution 1.76 Å Mutation No [2]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYCRSDPD
64
VERCLRAHRN
74
DMETIYPFLF
84
LGFVYSFLGP
94
NPFVAWMHFL
104

VFLVGRVAHT
114
VAYLGKLRAP
124
IRSVTYTLAQ
134
LPCASMALQI
144
LWEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.601
ASN74
2.905
GLU77
2.877
HIS113
2.770
Residue
Distance (Å)
TYR117
2.607
ARG126
2.806
SER127
3.232
TYR130
3.171
PDB ID: 5BQI      Discovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain
Method X-ray diffraction Resolution 1.88 Å Mutation No [5]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYCRSDPD
64
VERCLRAHRN
74
DMETIYPFLF
84
LGFVYSFLGP
94
NPFVAWMHFL
104

VFLVGRVAHT
114
VAYLGKLRAP
124
IRSVTYTLAQ
134
LPCASMALQI
144
LWEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.606
ASN74
2.868
GLU77
2.969
HIS113
2.853
Residue
Distance (Å)
TYR117
2.644
ARG126
2.863
SER127
3.399
TYR130
3.227
PDB ID: 4YL1      Crystal Structures of mPGES-1 Inhibitor Complexes
Method X-ray diffraction Resolution 1.41 Å Mutation No [4]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYCRSDPD
64
VERCLRAHRN
74
DMETIYPFLF
84
LGFVYSFLGP
94
NPFVAWMHFL
104

VFLVGRVAHT
114
VAYLGKLRAP
124
IRSVTYTLAQ
134
LPCASMALQI
144
LWEAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.648
ASN74
2.893
GLU77
2.909
HIS113
2.909
Residue
Distance (Å)
TYR117
2.601
ARG126
2.901
SER127
2.991
TYR130
3.214
PDB ID: 4YL3      Crystal Structures of mPGES-1 Inhibitor Complexes
Method X-ray diffraction Resolution 1.41 Å Mutation No [4]
PDB Sequence
VMSSPALPAF
16
LLCSTLLVIK
26
MYVVAIITGQ
36
VRLRKKAFAN
46
PEDALRHGGP
56

QYCRSDPDVE
66
RCLRAHRNDM
76
ETIYPFLFLG
86
FVYSFLGPNP
96
FVAWMHFLVF
106

LVGRVAHTVA
116
YLGKLRAPIR
126
SVTYTLAQLP
136
CASMALQILW
146
EAARHL
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
ARG70
3.654
ASN74
2.923
GLU77
3.157
HIS113
2.984
Residue
Distance (Å)
TYR117
2.547
ARG126
2.980
SER127
3.017
TYR130
3.187
PDB ID: 4YL0      Crystal Structures of mPGES-1 Inhibitor Complexes
Method X-ray diffraction Resolution 1.52 Å Mutation No [4]
PDB Sequence
SLVMSSPALP
14
AFLLCSTLLV
24
IKMYVVAIIT
34
GQVRLRKKAF
44
ANPEDALRHG
54

GPQYRSDPDV
65
ERCLRAHRND
75
METIYPFLFL
85
GFVYSFLGPN
95
PFVAWMHFLV
105

FLVGRVAHTV
115
AYLGKLRAPI
125
RSVTYTLAQL
135
PCASMALQIL
145
WEAARHL
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Residue
Distance (Å)
ARG70
3.604
ASN74
2.876
GLU77
3.043
HIS113
2.850
Residue
Distance (Å)
TYR117
2.589
ARG126
2.921
SER127
2.966
TYR130
3.185
PDB ID: 3DWW      Electron crystallographic structure of human microsomal prostaglandin E synthase 1
Method Electron crystallography Resolution N.A. Mutation No [6]
PDB Sequence
PALPAFLLCS
20
TLLVIKMYVV
30
AIITGQVRLR
40
KKAFANPEDA
50
LRHGGPQYCR
60

SDPDVERCLR
70
AHRNDMETIY
80
PFLFLGFVYS
90
FLGPNPFVAW
100
MHFLVFLVGR
110

VAHTVAYLGK
120
LRAPIRSVTY
130
TLAQLPCASM
140
ALQILWEAAR
150
HL
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Residue
Distance (Å)
ARG70
3.209
ARG73
4.530
ASN74
3.870
GLU77
2.625
ARG110
2.615
HIS113
2.200
TYR117
2.821
Residue
Distance (Å)
ARG126
2.662
THR129
4.777
TYR130
2.806
THR131
4.543
ALA133
4.053
GLN134
4.513
PDB ID: 4BPM      Crystal structure of a human integral membrane enzyme
Method X-ray diffraction Resolution 2.08 Å Mutation Yes [7]
PDB Sequence
SPALPAFLLC
19
STLLVIKMYV
29
VAIITGQVRL
39
RKKAFANPED
49
ALRHGGPQYC
59

RSDPDVERCL
69
RAHRNDMETI
79
YPFLFLGFVY
89
SFLGPNPFVA
99
WMHFLVFLVG
109

RVAHTVAYLG
119
KLRAPIRSVT
129
YTLAQLPCAS
139
MALQILWEAA
149
RHFLPAALRA
159

ALLGRLRTLR
169
PW
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Residue
Distance (Å)
ARG70
3.569
ARG73
2.867
ASN74
3.156
GLU77
3.185
HIS113
2.819
Residue
Distance (Å)
TYR117
2.463
ARG126
2.940
SER127
3.245
TYR130
3.383
PDB ID: 4WAB      Crystal structure of mPGES1 solved by native-SAD phasing
Method X-ray diffraction Resolution 2.70 Å Mutation No [8]
PDB Sequence
SPALPAFLLC
19
STLLVIKMYV
29
VAIITGQVRL
39
RKKAFANPED
49
ALRHGGPQYC
59

RSDPDVERCL
69
RAHRNDMETI
79
YPFLFLGFVY
89
SFLGPNPFVA
99
WMHFLVFLVG
109

RVAHTVAYLG
119
KLRAPIRSVT
129
YTLAQLPCAS
139
MALQILWEAA
149
RHFLPAALRA
159

ALLGRLRTLR
169
P
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Residue
Distance (Å)
ARG70
3.600
ARG73
2.647
ASN74
3.060
GLU77
3.080
HIS113
2.941
Residue
Distance (Å)
TYR117
2.584
ARG126
3.211
SER127
2.986
TYR130
3.218
References  Top
REF 1 Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3806-11.
REF 2 Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1. Bioorg Med Chem Lett. 2017 Mar 15;27(6):1478-1483.
REF 3 Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4824-4828.
REF 4 Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics. J Med Chem. 2015 Jun 11;58(11):4727-37.
REF 5 Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors. J Med Chem. 2016 Jan 14;59(1):194-205.
REF 6 Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11110-5.
REF 7 Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy. Cryst Growth Des. 2014 Apr 2;14(4):2034-2047.
REF 8 Fast native-SAD phasing for routine macromolecular structure determination. Nat Methods. 2015 Feb;12(2):131-3.

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