Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T39054 Target Info
Target Name dUTP pyrophosphatase (DUT)
Synonyms Deoxyuridine 5' triphosphate nucleotidohydrolase, mitochondrial; DUT
Target Type Clinical trial Target
Gene Name DUT
Biochemical Class Acid anhydrides hydrolase
UniProt ID
DUT_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: TAS-114 Ligand Info
Structure Description Crystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide PDB:5H4J
Method X-ray diffraction Resolution 1.80 Å Mutation No [1]
PDB Sequence
MQLRFARLSE
33
HATAPTRGSA
43
RAAGYDLYSA
53
YDYTIPPMEK
63
AVVKTDIQIA
73

LPSGCYGRVA
83
PRSGLAAKHF
93
IDVGAGVIDE
103
DYRGNVGVVL
113
FNFGKEKFEV
123

KKGDRIAQLI
133
CERIFYPEIE
143
EVQALD
Residue
Distance (Å)
VAL65
3.477
LYS67
3.916
VAL82
4.094
GLY97
4.238
ALA98
3.541
GLY99
2.905
VAL100
3.301
Residue
Distance (Å)
ILE101
3.818
TYR105
3.463
ASN108
3.526
VAL109
3.646
GLY110
2.702
VAL111
4.879
VAL112
3.432
Ligand Name: Deoxyuridine-5'-Diphosphate Ligand Info
Structure Description Human dUTP Pyrophosphatase complex with dUDP PDB:1Q5H
Method X-ray diffraction Resolution 2.00 Å Mutation No [2]
PDB Sequence
MQLRFARLSE
10
HATAPTRGSA
20
RAAGYDLYSA
30
YDYTIPPMEK
40
AVVKTDIQIA
50

LPSGCYGRVA
60
PRSGLAAKHF
70
IDVGAGVIDE
80
DYRGNVGVVL
90
FNFGKEKFEV
100

KKGDRIAQLI
110
CERIFYPEIE
120
EVQALDD
Residue
Distance (Å)
VAL59
4.458
GLY74
4.181
ALA75
3.532
GLY76
3.003
VAL77
3.418
ILE78
3.448
ASP79
2.802
Residue
Distance (Å)
TYR82
3.510
ASN85
3.730
VAL86
4.008
GLY87
2.725
VAL88
4.853
VAL89
4.402
Ligand Name: 1-[3-({(2r)-2-[hydroxy(Diphenyl)methyl]pyrrolidin-1-Yl}sulfonyl)propyl]pyrimidine-2,4(1h,3h)-Dione Ligand Info
Structure Description Discovery of Novel Uracil Derivatives as Potent Human dUTPase Inhibitors PDB:3ARA
Method X-ray diffraction Resolution 1.70 Å Mutation No [3]
PDB Sequence
MQLRFARLSE
33
HATAPTRGSA
43
RAAGYDLYSA
53
YDYTIPPMEK
63
AVVKTDIQIA
73

LPSGCYGRVA
83
PRSGLAAKHF
93
IDVGAGVIDE
103
DYRGNVGVVL
113
FNFGKEKFEV
123

KKGDRIAQLI
133
CERIFYPEIE
143
EVQAL
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .MKH or .MKH2 or .MKH3 or :3MKH;style chemicals stick;color identity;select .A:65 or .A:67 or .A:82 or .A:97 or .A:98 or .A:99 or .A:100 or .A:101 or .A:105 or .A:108 or .A:109 or .A:110 or .A:111 or .A:112; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL65
3.754
LYS67
3.841
VAL82
3.957
GLY97
4.218
ALA98
3.687
GLY99
2.919
VAL100
3.240
Residue
Distance (Å)
ILE101
3.868
TYR105
3.398
ASN108
3.809
VAL109
3.562
GLY110
2.713
VAL111
4.806
VAL112
3.448
Ligand Name: N-{5-[(2,4-Dioxo-3,4-Dihydropyrimidin-1(2h)-Yl)methoxy]-2-Methylpentan-2-Yl}benzenesulfonamide Ligand Info
Structure Description Human dUTPase in complex with novel uracil derivative PDB:3ARN
Method X-ray diffraction Resolution 1.80 Å Mutation No [4]
PDB Sequence
MQLRFARLSE
33
HATAPTRGSA
43
RAAGYDLYSA
53
YDYTIPPMEK
63
AVVKTDIQIA
73

LPSGCYGRVA
83
PRSGLAAKHF
93
IDVGAGVIDE
103
DYRGNVGVVL
113
FNFGKEKFEV
123

KKGDRIAQLI
133
CERIFYPEIE
143
EVQAL
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .MSJ or .MSJ2 or .MSJ3 or :3MSJ;style chemicals stick;color identity;select .A:65 or .A:82 or .A:97 or .A:98 or .A:99 or .A:100 or .A:101 or .A:105 or .A:108 or .A:109 or .A:110 or .A:111 or .A:112; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL65
3.743
VAL82
4.037
GLY97
4.240
ALA98
3.475
GLY99
2.869
VAL100
3.368
ILE101
3.907
Residue
Distance (Å)
TYR105
3.486
ASN108
3.738
VAL109
3.605
GLY110
2.707
VAL111
4.960
VAL112
3.434
References  Top
REF 1 TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy. Mol Cancer Ther. 2018 Aug;17(8):1683-1693.
REF 2 Human dUTP pyrophosphatase: uracil recognition by a beta hairpin and active sites formed by three separate subunits. Structure. 1996 Sep 15;4(9):1077-92.
REF 3 Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors. J Med Chem. 2012 Apr 12;55(7):2960-9.
REF 4 Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors. J Med Chem. 2012 Apr 12;55(7):2970-80.

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