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 T17345 Target Info
Target Name Dihydrofolate reductase (DHFR)
Synonyms DYR; DHFRP1
Target Type Successful Target
Gene Name DHFR
Biochemical Class CH-NH donor oxidoreductase
UniProt ID
DYR_HUMAN
Ligand General Information  Top
Ligand Name Folic acid Ligand Info
Canonical SMILES C1=CC(=CC=C1C(=O)NC(CCC(=O)O)C(=O)O)NCC2=CN=C3C(=N2)C(=O)NC(=N3)N
InChI 1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1
InChIKey OVBPIULPVIDEAO-LBPRGKRZSA-N
PubChem Compound ID 135398658
Drug Binding Sites of Target  Top
PDB ID: 2W3B      HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND A LIPOPHILIC ANTIFOLATE SELECTIVE FOR MYCOBACTERIUM AVIUM DHFR, 6-((2,5- DIETHOXYPHENYL)AMINOMETHYL)-2,4-DIAMINO-5-METHYLPYRIDO(2,3-D) PYRIMIDINE (SRI-8686)
Method X-ray diffraction Resolution 1.27 Å Mutation No [1]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DLPWPPLRNE
30
FRYFQRMTTT
40
SSVEGKQNLV
50

IMGKKTWFSI
60
PEKNRPLKGR
70
INLVLSRELK
80
EPPQGAHFLS
90
RSLDDALKLT
100

EQPELANKVD
110
MVWIVGGSSV
120
YKEAMNHPGH
130
LKLFVTRIMQ
140
DFESDTFFPE
150

IDLEKYKLLP
160
EYPGVLSDVQ
170
EEKGIKYKFE
180
VYEKN
Residue
Distance (Å)
ILE7
3.363
VAL8
3.620
ALA9
3.609
LEU22
3.934
ARG28
4.531
GLU30
2.533
PHE31
3.622
ARG32
3.615
TYR33
4.502
PHE34
3.351
GLN35
0.860
Residue
Distance (Å)
THR56
3.830
SER59
4.279
ILE60
3.439
PRO61
3.763
ASN64
2.925
LEU67
3.570
LYS68
4.546
ARG70
2.906
VAL115
2.875
TYR121
3.787
THR136
3.640
PDB ID: 4M6K      Crystal structure of human dihydrofolate reductase (DHFR) bound to NADP+ and folate
Method X-ray diffraction Resolution 1.40 Å Mutation No [2]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DLPWPPLRNE
30
FRYFQRMTTT
40
SSVEGKQNLV
50

IMGKKTWFSI
60
PEKNRPLKGR
70
INLVLSRELK
80
EPPQGAHFLS
90
RSLDDALKLT
100

EQPELANKVD
110
MVWIVGGSSV
120
YKEAMNHPGH
130
LKLFVTRIMQ
140
DFESDTFFPE
150

IDLEKYKLLP
160
EYPGVLSDVQ
170
EEKGIKYKFE
180
VYEKND
Residue
Distance (Å)
ILE7
3.511
VAL8
3.525
ALA9
3.584
LEU22
3.448
ARG28
4.294
GLU30
2.760
PHE31
3.355
ARG32
3.438
TYR33
4.531
PHE34
3.379
GLN35
2.903
THR38
4.908
Residue
Distance (Å)
THR56
3.924
SER59
4.314
ILE60
3.881
PRO61
3.900
ASN64
2.931
LEU67
3.620
LYS68
4.643
ARG70
2.802
VAL115
3.274
TYR121
3.749
THR136
3.663
PDB ID: 2W3M      HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND FOLATE
Method X-ray diffraction Resolution 1.60 Å Mutation No [3]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DLPWPPLRNE
30
FRYFQRMTTT
40
SSVEGKQNLV
50

IMGKKTWFSI
60
PEKNRPLKGR
70
INLVLSRELK
80
EPPQGAHFLS
90
RSLDDALKLT
100

EQPELANKVD
110
MVWIVGGSSV
120
YKEAMNHPGH
130
LKLFVTRIMQ
140
DFESDTFFPE
150

IDLEKYKLLP
160
EYPGVLSDVQ
170
EEKGIKYKFE
180
VYEKND
Residue
Distance (Å)
ILE7
3.482
VAL8
3.600
ALA9
3.654
LEU22
3.673
ARG28
4.766
GLU30
2.760
PHE31
3.440
ARG32
4.059
TYR33
4.635
PHE34
3.387
GLN35
2.891
THR38
4.869
Residue
Distance (Å)
THR56
4.102
SER59
4.256
ILE60
3.756
PRO61
3.958
ASN64
3.172
LEU67
3.621
LYS68
4.495
ARG70
2.848
VAL115
3.286
TYR121
3.848
THR136
3.667
PDB ID: 1DRF      CRYSTAL STRUCTURE OF HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE
Method X-ray diffraction Resolution 2.00 Å Mutation No [4]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DLPWPPLRNE
30
FRYFQRMTTT
40
SSVEGKQNLV
50

IMGKKTWFSI
60
PEKNRPLKGR
70
INLVLSRELK
80
EPPQGAHFLS
90
RSLDDALKLT
100

EQPELANKVD
110
MVWIVGGSSV
120
YKEAMNHPGH
130
LKLFVTRIMQ
140
DFESDTFFPE
150

IDLEKYKLLP
160
EYPGVLSDVQ
170
EEKGIKYKFE
180
VYEKND
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOL or .FOL2 or .FOL3 or :3FOL;style chemicals stick;color identity;select .A:7 or .A:8 or .A:9 or .A:22 or .A:28 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:38 or .A:56 or .A:59 or .A:60 or .A:61 or .A:64 or .A:67 or .A:68 or .A:70 or .A:115 or .A:116 or .A:121 or .A:136; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE7
3.491
VAL8
3.271
ALA9
3.304
LEU22
3.999
ARG28
4.176
GLU30
2.702
PHE31
3.413
ARG32
3.929
TYR33
4.691
PHE34
2.958
GLN35
3.305
THR38
4.811
Residue
Distance (Å)
THR56
4.094
SER59
3.884
ILE60
3.501
PRO61
3.752
ASN64
2.865
LEU67
3.989
LYS68
4.782
ARG70
2.778
VAL115
2.895
GLY116
4.964
TYR121
3.581
THR136
3.235
PDB ID: 1DHF      CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE
Method X-ray diffraction Resolution 2.30 Å Mutation No [5]
PDB Sequence
LNCIVAVSQN
13
MGIGKNGDLP
23
WPPLRNEFRY
33
FQRMTTTSSV
43
EGKQNLVIMG
53

KKTWFSIPEK
63
NRPLKGRINL
73
VLSRELKEPP
83
QGAHFLSRSL
93
DDALKLTEQP
103

ELANKVDMVW
113
IVGGSSVYKE
123
AMNHPGHLKL
133
FVTRIMQDFE
143
SDTFFPEIDL
153

EKYKLLPEYP
163
GVLSDVQEEK
173
GIKYKFEVYE
183
KN
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOL or .FOL2 or .FOL3 or :3FOL;style chemicals stick;color identity;select .A:7 or .A:8 or .A:9 or .A:28 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:56 or .A:59 or .A:60 or .A:61 or .A:64 or .A:67 or .A:70 or .A:115 or .A:121 or .A:136; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE7
3.462
VAL8
3.548
ALA9
3.691
ARG28
4.472
GLU30
2.682
PHE31
3.298
ARG32
3.431
TYR33
4.540
PHE34
3.182
GLN35
3.025
Residue
Distance (Å)
THR56
3.752
SER59
3.921
ILE60
3.646
PRO61
3.577
ASN64
3.382
LEU67
3.581
ARG70
2.933
VAL115
3.204
TYR121
3.653
THR136
3.396
PDB ID: 6VCJ      Crystal structure of hsDHFR in complex with NADP+, DAP, and R-naproxen
Method X-ray diffraction Resolution 2.34 Å Mutation No [6]
PDB Sequence
SLNCIVAVSQ
12
NMGIGKNGDL
22
PWPPLRNEFR
32
YFQRMTTTSS
42
VEGKQNLVIM
52

GKKTWFSIPE
62
KNRPLKGRIN
72
LVLSRELKEP
82
PQGAHFLSRS
92
LDDALKLTEQ
102

PELANKVDMV
112
WIVGGSSVYK
122
EAMNHPGHLK
132
LFVTRIMQDF
142
ESDTFFPEID
152

LEKYKLLPEY
162
PGVLSDVQEE
172
KGIKYKFEVY
182
EKND
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOL or .FOL2 or .FOL3 or :3FOL;style chemicals stick;color identity;select .A:7 or .A:8 or .A:9 or .A:22 or .A:28 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:56 or .A:59 or .A:60 or .A:61 or .A:64 or .A:67 or .A:68 or .A:70 or .A:115 or .A:121 or .A:136; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE7
3.588
VAL8
3.537
ALA9
3.706
LEU22
3.688
ARG28
4.642
GLU30
2.829
PHE31
3.011
ARG32
4.439
TYR33
4.813
PHE34
3.225
GLN35
2.647
Residue
Distance (Å)
THR56
4.025
SER59
4.158
ILE60
4.067
PRO61
4.152
ASN64
2.734
LEU67
3.654
LYS68
4.633
ARG70
2.589
VAL115
3.393
TYR121
4.015
THR136
3.748
PDB ID: 7ESE      The Crystal Structure of human DHFR from Biortus
Method X-ray diffraction Resolution 1.85 Å Mutation No [7]
PDB Sequence
GSLNCIVAVS
12
QNMGIGKNGD
22
LPWPPLRNEF
32
RYFQRMTTTS
42
SVEGKQNLVI
52

MGKKTWFSIP
62
EKNRPLKGRI
72
NLVLSRELKE
82
PPQGAHFLSR
92
SLDDALKLTE
102

QPELANKVDM
112
VWIVGGSSVY
122
KEAMNHPGHL
132
KLFVTRIMQD
142
FESDTFFPEI
152

DLEKYKLLPE
162
YPGVLSDVQE
172
EKGIKYKFEV
182
YEKND
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOL or .FOL2 or .FOL3 or :3FOL;style chemicals stick;color identity;select .A:8 or .A:9 or .A:10 or .A:23 or .A:25 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:36 or .A:39 or .A:57 or .A:60 or .A:61 or .A:62 or .A:65 or .A:68 or .A:69 or .A:71 or .A:116 or .A:122 or .A:137; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE8
3.477
VAL9
3.502
ALA10
3.495
LEU23
4.232
TRP25
4.917
GLU31
2.670
PHE32
3.374
ARG33
4.746
TYR34
4.502
PHE35
3.329
GLN36
3.305
THR39
4.857
Residue
Distance (Å)
THR57
3.868
SER60
4.126
ILE61
4.098
PRO62
4.229
ASN65
2.906
LEU68
3.724
LYS69
4.745
ARG71
2.734
VAL116
3.373
TYR122
3.701
THR137
3.554
References  Top
REF 1 HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND A LIPOPHILIC ANTIFOLATE SELECTIVE FOR MYCOBACTERIUM AVIUM DHFR, 6-((2,5- DIETHOXYPHENYL)AMINOMETHYL)-2,4-DIAMINO-5-METHYLPYRIDO(2,3-D) PYRIMIDINE (SRI-8686)
REF 2 Divergent evolution of protein conformational dynamics in dihydrofolate reductase. Nat Struct Mol Biol. 2013 Nov;20(11):1243-9.
REF 3 HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND FOLATE
REF 4 Crystal structure of human dihydrofolate reductase complexed with folate. Eur J Biochem. 1988 Jun 1;174(2):377-85.
REF 5 Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. Biochemistry. 1990 Oct 9;29(40):9467-79.
REF 6 The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. J Med Chem. 2020 Aug 13;63(15):8314-8324.
REF 7 The Crystal Structure of human DHFR from Biortus

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