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 T02702 Target Info
Target Name Bacterial Dihydrofolate reductase (Bact DHFR)
Synonyms Bact Dihydrofolate reductase
Target Type Clinical trial Target
Gene Name Bact DHFR
UniProt ID
DYR_ECOLI
Ligand General Information  Top
Ligand Name 5,10-Dideazatetrahydrofolic acid Ligand Info
Canonical SMILES C1C(CNC2=C1C(=O)NC(=N2)N)CCC3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
InChI 1S/C21H25N5O6/c22-21-25-17-14(19(30)26-21)9-12(10-23-17)2-1-11-3-5-13(6-4-11)18(29)24-15(20(31)32)7-8-16(27)28/h3-6,12,15H,1-2,7-10H2,(H,24,29)(H,27,28)(H,31,32)(H4,22,23,25,26,30)/t12?,15-/m0/s1
InChIKey ZUQBAQVRAURMCL-CVRLYYSRSA-N
PubChem Compound ID 135400183
Drug Binding Sites of Target  Top
PDB ID: 5CC9      L28F E.coli dihydrofolate reductase complexed with 5,10-dideazatetrahydrofolate and oxidized nicotinamide adenine dinucleotide phosphate
Method X-ray diffraction Resolution 1.20 Å Mutation Yes [1]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADFAW
30
FKRNTLNKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Residue
Distance (Å)
ILE5
1.902
ALA6
2.604
ALA7
2.604
GLY15
4.415
MET20
4.820
TRP22
3.666
ASP27
2.017
PHE28
2.083
ALA29
4.666
TRP30
2.596
PHE31
2.562
LYS32
2.536
THR35
4.417
Residue
Distance (Å)
LEU36
4.515
THR46
3.833
ILE50
1.988
LEU54
2.946
PRO55
3.558
ARG57
1.673
ILE94
2.199
GLY95
4.097
TYR100
2.795
TYR111
4.724
THR113
2.461
PHE153
4.347
PDB ID: 5CCC      wild-type E.coli dihydrofolate reductase complexed with 5,10-dideazatetrahydrofolate and oxidized nicotinamide adenine dinucleotide phosphate
Method X-ray diffraction Resolution 1.50 Å Mutation No [1]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLNKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Residue
Distance (Å)
ILE5
1.948
ALA6
2.592
ALA7
2.539
GLY15
4.105
MET16
4.803
GLU17
3.651
MET20
2.212
TRP22
3.449
ASP27
1.924
LEU28
2.262
TRP30
2.656
PHE31
2.535
LYS32
2.739
THR35
4.911
Residue
Distance (Å)
THR46
3.378
SER49
4.337
ILE50
3.034
LEU54
2.738
PRO55
3.184
ARG57
1.856
ILE94
2.208
GLY95
3.918
GLY96
4.903
TYR100
2.493
TYR111
4.710
THR113
2.442
PHE153
4.367
PDB ID: 1DYJ      ISOMORPHOUS CRYSTAL STRUCTURES OF ESCHERICHIA COLI DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE, 5-DEAZAFOLATE AND 5,10-DIDEAZATETRAHYDROFOLATE: MECHANISTIC IMPLICATIONS
Method X-ray diffraction Resolution 1.85 Å Mutation No [2]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLDKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Residue
Distance (Å)
ILE5
3.228
ALA6
3.755
ALA7
3.354
TRP22
4.936
ASP27
2.636
LEU28
3.757
ALA29
4.384
TRP30
3.993
PHE31
3.191
LYS32
3.679
Residue
Distance (Å)
THR35
4.646
THR46
4.594
ILE50
3.798
ARG52
2.994
LEU54
3.716
PRO55
4.409
ARG57
2.462
ILE94
2.952
TYR100
3.392
THR113
3.644
PDB ID: 1RC4      DIHYDROFOLATE REDUCTASE COMPLEXED WITH 5,10-DIDEAZATETRAHYDROFOLATE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (OXIDIZED FORM)
Method X-ray diffraction Resolution 1.90 Å Mutation No [3]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLDKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DDF or .DDF2 or .DDF3 or :3DDF;style chemicals stick;color identity;select .A:5 or .A:6 or .A:7 or .A:17 or .A:27 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:35 or .A:46 or .A:50 or .A:52 or .A:54 or .A:55 or .A:57 or .A:94 or .A:100 or .A:113; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE5
3.364
ALA6
3.666
ALA7
3.484
GLU17
4.139
ASP27
2.723
LEU28
3.277
ALA29
4.917
TRP30
3.954
PHE31
3.371
LYS32
3.511
Residue
Distance (Å)
THR35
4.589
THR46
4.745
ILE50
4.015
ARG52
4.077
LEU54
3.801
PRO55
4.302
ARG57
2.602
ILE94
3.375
TYR100
3.500
THR113
3.710
PDB ID: 1RX6      DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH 5,10-DIDEAZATETRAHYDROFOLATE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (REDUCED FORM)
Method X-ray diffraction Resolution 2.00 Å Mutation No [3]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLDKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DDF or .DDF2 or .DDF3 or :3DDF;style chemicals stick;color identity;select .A:5 or .A:6 or .A:7 or .A:17 or .A:27 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:35 or .A:46 or .A:50 or .A:54 or .A:55 or .A:57 or .A:94 or .A:100 or .A:113; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE5
2.985
ALA6
3.455
ALA7
3.411
GLU17
3.675
ASP27
2.869
LEU28
3.971
ALA29
4.690
TRP30
3.881
PHE31
3.313
LYS32
3.151
Residue
Distance (Å)
THR35
4.768
THR46
4.823
ILE50
4.338
LEU54
3.881
PRO55
4.276
ARG57
2.474
ILE94
3.263
TYR100
3.278
THR113
3.446
PDB ID: 1RX4      DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH 5,10-DIDEAZATETRAHYDROFOLATE AND 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE
Method X-ray diffraction Resolution 2.20 Å Mutation No [3]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLDKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DDF or .DDF2 or .DDF3 or :3DDF;style chemicals stick;color identity;select .A:5 or .A:6 or .A:7 or .A:16 or .A:17 or .A:27 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:35 or .A:46 or .A:50 or .A:52 or .A:54 or .A:55 or .A:57 or .A:94 or .A:100 or .A:113; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE5
2.791
ALA6
3.369
ALA7
3.526
MET16
3.904
GLU17
2.853
ASP27
2.867
LEU28
4.113
ALA29
4.712
TRP30
4.028
PHE31
3.312
LYS32
2.770
Residue
Distance (Å)
THR35
4.772
THR46
4.866
ILE50
4.341
ARG52
3.024
LEU54
3.892
PRO55
4.355
ARG57
2.589
ILE94
2.861
TYR100
3.171
THR113
3.472
PDB ID: 1RX5      DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH 5,10-DIDEAZATETRAHYDROFOLATE
Method X-ray diffraction Resolution 2.30 Å Mutation No [3]
PDB Sequence
MISLIAALAV
10
DRVIGMENAM
20
PWNLPADLAW
30
FKRNTLDKPV
40
IMGRHTWESI
50

GRPLPGRKNI
60
ILSSQPGTDD
70
RVTWVKSVDE
80
AIAACGDVPE
90
IMVIGGGRVY
100

EQFLPKAQKL
110
YLTHIDAEVE
120
GDTHFPDYEP
130
DDWESVFSEF
140
HDADAQNSHS
150

YCFEILERR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DDF or .DDF2 or .DDF3 or :3DDF;style chemicals stick;color identity;select .A:5 or .A:6 or .A:7 or .A:16 or .A:17 or .A:22 or .A:27 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:35 or .A:46 or .A:50 or .A:52 or .A:54 or .A:55 or .A:57 or .A:94 or .A:100 or .A:113; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE5
2.930
ALA6
3.158
ALA7
3.321
MET16
3.796
GLU17
4.906
TRP22
4.879
ASP27
2.809
LEU28
3.747
ALA29
4.563
TRP30
3.995
PHE31
3.191
Residue
Distance (Å)
LYS32
2.820
THR35
4.773
THR46
3.972
ILE50
3.876
ARG52
3.269
LEU54
3.863
PRO55
4.124
ARG57
2.715
ILE94
2.955
TYR100
3.403
THR113
3.224
References  Top
REF 1 Cofactor-Mediated Conformational Dynamics Promote Product Release From Escherichia coli Dihydrofolate Reductase via an Allosteric Pathway. J Am Chem Soc. 2015 Jul 29;137(29):9459-68.
REF 2 Isomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications. Biochemistry. 1995 Feb 28;34(8):2710-23.
REF 3 Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence. Biochemistry. 1997 Jan 21;36(3):586-603.

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