Target Binding Site Detail
| 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 | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Methotrexate | Ligand Info | |||
| Canonical SMILES | CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O | ||||
| InChI | 1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1 | ||||
| InChIKey | FBOZXECLQNJBKD-ZDUSSCGKSA-N | ||||
| PubChem Compound ID | 126941 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 3EIG Crystal structure of a methotrexate-resistant mutant of human dihydrofolate reductase | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [1] |
| PDB Sequence |
VGSLNCIVAV
10 SQNMGIGKNG20 DLPWPPLRNE30 RRYFERMTTT40 SSVEGKQNLV50 IMGKKTWFSI 60 PEKNRPLKGR70 INLVLSRELK80 EPPQGAHFLS90 RSLDDALKLT100 EQPELANKVD 110 MVWIVGGSSV120 YKEAMNHPGH130 LKLFVTRIMQ140 DFESDTFFPE150 IDLEKYKLLP 160 EYPGVLSDVQ170 EEKGIKYKFE180 VYEKND
|
|||||
|
|
ILE7
2.909
VAL8
3.452
ALA9
3.635
ASP21
3.899
LEU22
3.720
ARG28
4.108
GLU30
2.656
ARG31
3.454
ARG32
3.246
TYR33
4.689
PHE34
3.510
GLU35
3.140
THR38
4.893
|
|||||
| PDB ID: 1U72 Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrfolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [2] |
| PDB Sequence |
VGSLNCIVAV
10 SQNMGIGKNG20 DLPWPPLRNE30 FRYFQRMTTT40 SSVEGKQNLV50 IMGKKTWFSI 60 PEKNRPLKGR70 INLVLSRELK80 EPPQGAHFLS90 RSLDDALKLT100 EQPELANKVD 110 MVWIVGGSSV120 YKEAMNHPGH130 LKLFVTRIMQ140 DFESDTFFPE150 IDLEKYKLLP 160 EYPGVLSDVQ170 EEKGIKYKFE180 VYEKND
|
|||||
|
|
ILE7
2.716
VAL8
3.244
ALA9
3.561
ASP21
4.735
LEU22
3.628
ARG28
4.859
GLU30
2.935
PHE31
3.436
ARG32
4.230
PHE34
3.498
GLN35
3.285
|
|||||
| PDB ID: 1DLS 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 | [3] |
| PDB Sequence |
VGSLNCIVAV
10 SQNMGIGKNG20 DYPWPPLRNE30 FRYFQRMTTT40 SSVEGKQNLV50 IMGKKTWFSI 60 PEKNRPLKGR70 INLVLSRELK80 EPPQGAHFLS90 RSLDDALKLT100 EQPELANKVD 110 MVWIVGGSSV120 YKEAMNHPGH130 LKLFVTRIMQ140 DFESDTFFPE150 IDLEKYKLLP 160 EYPGVLSDVQ170 EEKGIKYKFE180 VYEKND
|
|||||
|
|
ILE7
2.886
VAL8
3.368
ALA9
3.634
ASP21
4.673
TYR22
3.954
ARG28
3.130
GLU30
2.695
PHE31
3.233
ARG32
4.126
TYR33
4.729
PHE34
3.172
GLN35
3.579
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance. J Biol Chem. 2009 Jul 24;284(30):20079-89. | ||||
| REF 2 | 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 3 | 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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