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 Piritrexim Ligand Info
Canonical SMILES CC1=C2C(=NC(=NC2=NC=C1CC3=C(C=CC(=C3)OC)OC)N)N
InChI 1S/C17H19N5O2/c1-9-11(6-10-7-12(23-2)4-5-13(10)24-3)8-20-16-14(9)15(18)21-17(19)22-16/h4-5,7-8H,6H2,1-3H3,(H4,18,19,20,21,22)
InChIKey VJXSSYDSOJBUAV-UHFFFAOYSA-N
PubChem Compound ID 54369
Drug Binding Sites of Target  Top
PDB ID: 1U71      Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH
Method X-ray diffraction Resolution 2.20 Å Mutation Yes [1]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DRPWPPLRNE
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
3.041
VAL8
3.431
ALA9
3.600
ILE16
4.751
GLY20
3.372
ASP21
3.495
ARG22
3.163
GLU30
2.738
PHE31
3.618
TYR33
4.805
Residue
Distance (Å)
PHE34
3.540
THR56
4.155
SER59
3.314
ILE60
4.270
PRO61
3.475
ASN64
3.419
VAL115
3.195
TYR121
3.470
THR136
3.659
PDB ID: 1DLR      METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS
Method X-ray diffraction Resolution 2.30 Å Mutation No [2]
PDB Sequence
VGSLNCIVAV
10
SQNMGIGKNG
20
DFPWPPLRNE
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
2.972
VAL8
3.433
ALA9
3.588
PHE22
2.956
GLU30
2.650
PHE31
3.684
TYR33
4.927
PHE34
3.521
THR56
4.471
Residue
Distance (Å)
SER59
3.729
ILE60
3.768
PRO61
3.487
ASN64
3.752
VAL115
3.084
GLY116
4.923
TYR121
4.045
THR136
3.560
References  Top
REF 1 Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH. Acta Crystallogr D Biol Crystallogr. 2005 Feb;61(Pt 2):147-55.
REF 2 Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers. J Biol Chem. 1995 Mar 10;270(10):5057-64.

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