Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T98397 | Target Info | |||
| Target Name | Thymidylate synthase (TYMS) | ||||
| Synonyms | TSase; TS | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | TYMS | ||||
| Biochemical Class | Methyltransferase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Raltitrexed | Ligand Info | |||
| Canonical SMILES | CC1=NC2=C(C=C(C=C2)CN(C)C3=CC=C(S3)C(=O)NC(CCC(=O)O)C(=O)O)C(=O)N1 | ||||
| InChI | 1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1 | ||||
| InChIKey | IVTVGDXNLFLDRM-HNNXBMFYSA-N | ||||
| PubChem Compound ID | 135400182 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 6ZXO Crystal structure of His-tagged human thymidylate synthase (HT-hTS) in complex with FdUMP and Raltitrexed (Tomudex) | ||||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [1] |
| PDB Sequence |
> Chain A
PPHGELQYLG 35 QIQHILRCGV45 RKDDRTGTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKG105 VKIWDANGSR115 DFLDSLGFST125 REEGDLGPVY 135 GFQWRHFGAE145 YRDMESDYSG155 QGVDQLQRVI165 DTIKTNPDDR175 RIIMCAWNPR 185 DLPLMALPPC195 HALCQFYVVN205 SELSCQLYQR215 SGDMGLGVPF225 NIASYALLTY 235 MIAHITGLKP245 GDFIHTLGDA255 HIYLNHIEPL265 KIQLQREPRP275 FPKLRILRKV 285 EKIDDFKAED295 FQIEGYNPHP305 TIKMEMAV> Chain F PPHGELQYLG 35 QIQHILRCGV45 RKDDRTGTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKG105 VKIWDANGSR115 DFLDSLGFST125 REEGDLGPVY 135 GFQWRHFGAE145 YRDMESDYSG155 QGVDQLQRVI165 DTIKTNPDDR175 RIIMCAWNPR 185 DLPLMALPPC195 HALQFYVVNS206 ELSCQLYQRS216 GDMGLGVPFN226 IASYALLTYM 236 IAHITGLKPG246 DFIHTLGDAH256 IYLNHIEPLK266 IQLQREPRPF276 PKLRILRKVE 286 KIDDFKAEDF296 QIEGYNPHPT306 IKMEMA
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PHE80[A]
3.826
GLU87[A]
4.416
ILE108[A]
3.737
TRP109[A]
3.725
ASN112[A]
4.865
LEU192[A]
4.631
ASP218[A]
2.839
LEU221[A]
3.396
GLY222[A]
2.848
PHE225[A]
3.359
ASN226[A]
3.816
TYR258[A]
3.835
MET311[A]
3.772
ALA312[A]
3.712
ARG50[F]
4.703
THR51[F]
4.763
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| PDB ID: 1I00 CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [2] |
| PDB Sequence |
SELQYLGQIQ
38 HILRCGVRKD48 DRTGTGTLSV58 FGMQARYSLR68 DEFPLLTTKR78 VFWKGVLEEL 88 LWFIKGSTNA98 KELSSKGVKI108 WDANGSRDFL118 DSLGFSTREE128 GDLGPVYGFQ 138 WRHFGAEYRD148 MESDYSGQGV158 DQLQRVIDTI168 KTNPDDRRII178 MCAWNPRDLP 188 LMALPPCHAL198 CQFYVVNSEL208 SCQLYQRSGD218 MGLGVPFNIA228 SYALLTYMIA 238 HITGLKPGDF248 IHTLGDAHIY258 LNHIEPLKIQ268 LQREPRPFPK278 LRILRKVEKI 288 DDFKAEDFQI298 EGYNPHPT
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| PDB ID: 5X5Q Human thymidylate synthase complexed with dUMP and raltitrexed | ||||||
| Method | X-ray diffraction | Resolution | 2.79 Å | Mutation | No | [3] |
| PDB Sequence |
PPHGELQYLG
35 QIQHILRCGV45 RKDDRTGTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKG105 VKIWDANGSR115 DFLDSLGFST125 REEGDLGPVY 135 GFQWRHFGAE145 YRDMESDYSG155 QGVDQLQRVI165 DTIKTNPDDR175 RIIMCAWNPR 185 DLPLMALPPC195 HALCQFYVVN205 SELSCQLYQR215 SGDMGLGVPF225 NIASYALLTY 235 MIAHITGLKP245 GDFIHTLGDA255 HIYLNHIEPL265 KIQLQREPRP275 FPKLRILRKV 285 EKIDDFKAED295 FQIEGYNPHP305 TIKMEM
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| PDB ID: 1HVY Human thymidylate synthase complexed with dUMP and Raltitrexed, an antifolate drug, is in the closed conformation | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [4] |
| PDB Sequence |
PPHGELQYLG
35 QIQHILRGVR46 KDDRTGTGTL56 SVFGMQARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSSKGV106 KIWDANGSRD116 FLDSLGFSTR126 EEGDLGPVYG 136 FQWRHFGAEY146 RDMESDYSGQ156 GVDQLQRVID166 TIKTNPDDRR176 IIMCAWNPRD 186 LPLMALPPCH196 ALCQFYVVNS206 ELSCQLYQRS216 GDMGLGVPFN226 IASYALLTYM 236 IAHITGLKPG246 DFIHTLGDAH256 IYLNHIEPLK266 IQLQREPRPF276 PKLRILRKVE 286 KIDDFKAEDF296 QIEGYNPHPT306 IKMEMAV
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Click to Show 3D Structure of This Binding Site
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations. Cancers (Basel). 2021 Apr 24;13(9):2061. | ||||
| REF 2 | Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP. Protein Sci. 2001 May;10(5):988-96. | ||||
| REF 3 | Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states. J Biol Chem. 2017 Aug 11;292(32):13449-13458. | ||||
| REF 4 | Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug. Biochemistry. 2001 Feb 20;40(7):1897-902. | ||||
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