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 | S,S-(2-Hydroxyethyl)Thiocysteine | Ligand Info | |||
| Canonical SMILES | C(CSSCC(C(=O)O)N)O | ||||
| InChI | 1S/C5H11NO3S2/c6-4(5(8)9)3-11-10-2-1-7/h4,7H,1-3,6H2,(H,8,9)/t4-/m0/s1 | ||||
| InChIKey | YPUBRSXDQSFQBA-BYPYZUCNSA-N | ||||
| PubChem Compound ID | 170018 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 4G2O Human Thymidylate Synthase M190K with bound Purpurogallin | ||||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | Yes | [1] |
| PDB Sequence |
PHGELQYLGQ
36 IQHILRCGVR46 KDDRTGTGTL56 SVFGMQARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSSKGV106 LDSLGFSTRE127 EGDLGPVYGF137 QWRHFGAEYR 147 DMESDYSGQG157 VDQLQRVIDT167 IKTNPDDRRI177 IMAWNPRDLP188 LKALPPHALC 199 QFYVVNSELS209 CQLYQRSGDM219 GLGVPFNIAS229 YALLTYMIAH239 ITGLKPGDFI 249 HTLGDAHIYL259 NHIEPLKIQL269 QREPRPFPKL279 RILRKVEKID289 DFKAEDFQIE 299 GYNPHPTIKM309 E
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| PDB ID: 4GD7 Wild-Type Human Thymidylate Synthase with bound Purpurogallin | ||||||
| Method | X-ray diffraction | Resolution | 2.29 Å | Mutation | No | [2] |
| PDB Sequence |
PHGELQYLGQ
36 IQHILRGVRK47 DDRTGTGTLS57 VFGMQARYSL67 RDEFPLLTTK77 RVFWKGVLEE 87 LLWFIKGSTN97 AKELSSKGVL118 DSLGFSTREE128 GDLGPVYGFQ138 WRHFGAEYRD 148 MESDYSGQGV158 DQLQRVIDTI168 KTNPDDRRII178 MAWNPRDLPL189 MALPPHALCQ 200 FYVVNSELSC210 QLYQRSGDMG220 LGVPFNIASY230 ALLTYMIAHI240 TGLKPGDFIH 250 TLGDAHIYLN260 HIEPLKIQLQ270 REPRPFPKLR280 ILRKVEKIDD290 FKAEDFQIEG 300 YNPHPTIKME310
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| PDB ID: 4G6W Human Thymidylate Synthase M190K with bound 4-Bromobenzene-1,2,3-triol | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [3] |
| PDB Sequence |
PHGELQYLGQ
36 IQHILRCGVR46 KDDRTGTGTL56 SVFGMQARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSFLDS120 LGFSTREEGD130 LGPVYGFQWR140 HFGAEYRDME 150 SDYSGQGVDQ160 LQRVIDTIKT170 NPDDRRIIMA181 WNPRDLPLKA191 LPPHALCQFY 202 VVNSELSCQL212 YQRSGDMGLG222 VPFNIASYAL232 LTYMIAHITG242 LKPGDFIHTL 252 GDAHIYLNHI262 EPLKIQLQRE272 PRPFPKLRIL282 RKVEKIDDFK292 AEDFQIEGYN 302 PHPTIKME
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| PDB ID: 2ONB Human Thymidylate Synthase at low salt conditions with PDPA bound | ||||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | Yes | [4] |
| PDB Sequence |
PPHGELQYLG
35 QIQHILRGVR46 KDDRTGTGTL56 SVFGMQARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSSKGV106 KGDLGPVYGF137 QWRHFGAEYR147 DMESDYSGQG 157 VDQLQRVIDT167 IKTNPDDRRI177 IMAWNPRDLP188 LMALPPHALQ200 FYVVNSELSC 210 QLYQRSGDMG220 LGVPFNIASY230 ALLTYMIAHI240 TGLKPGDFIH250 TLGDAHIYLN 260 HIEPLKIQLQ270 REPRPFPKLR280 ILRKVEKIDD290 FKAEDFQIEG300 YNPHPTIKME 310
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .A:38 or .A:39 or .A:40 or .A:41 or .A:42 or .A:44 or .A:45 or .A:58 or .A:139 or .A:142 or .A:160 or .A:177 or .A:178 or .A:179 or .A:181 or .A:182 or .A:193 or .A:194 or .A:196 or .A:197 or .A:198 or .A:200 or .A:201 or .A:210 or .A:211 or .A:212 or .A:213 or .A:214 or .A:215 or .A:230 or .A:233; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLN38
4.536
HIS39
2.669
ILE40
3.552
LEU41
3.513
ARG42
1.334
GLY44
1.319
VAL45
3.982
VAL58
4.306
TRP139
3.211
PHE142
3.890
GLN160
3.096
ILE177
4.749
ILE178
4.167
MET179
1.333
ALA181
1.328
TRP182
2.788
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| PDB ID: 6QYQ Crystal structure of human thymidylate synthase (hTS) variant R175C | ||||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | Yes | [5] |
| PDB Sequence |
> Chain A
EPRPPHGELQ 32 YLGQIQHILR42 CGVRKDDTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKG105 VKIWDANGSR115 DFLDSLGFST125 REEGDLGPVY 135 GFQWRHFGAE145 YRDMESDYSG155 QGVDQLQRVI165 DTIKTNPDDC175 RIIMAWNPRD 186 LPLMALPPHA197 LQFYVVNSEL208 SCQLYQRSGD218 MGLGVPFNIA228 SYALLTYMIA 238 HITGLKPGDF248 IHTLGDAHIY258 LNHIEPLKIQ268 LQREPRPFPK278 LRILRKVEKI 288 DDFKAEDFQI298 EGYNPHPTIK308 MEM> Chain B PRPPHGELQY 33 LGQIQHILRG44 VRKDDRTGTG54 TLSVFGMQAR64 YSLRDEFPLL74 TTKRVFWKGV 84 LEELLWFIKG94 STNAKELSSK104 GVKIWDANGS114 RDFLDSLGFS124 TREEGDLGPV 134 YGFQWRHFGA144 EYRDMESDYS154 GQGVDQLQRV164 IDTIKTNPDD174 CRIIMAWNPR 185 DLPLMALPPH196 ALQFYVVNSE207 LSCQLYQRSG217 DMGLGVPFNI227 ASYALLTYMI 237 AHITGLKPGD247 FIHTLGDAHI257 YLNHIEPLKI267 QLQREPRPFP277 KLRILRKVEK 287 IDDFKAEDFQ297 IEGYNPHPTI307 KMEMA> Chain C PRPPHGELQY 33 LGQIQHILRG44 VRKDTGTLSV58 FGMQARYSLR68 DEFPLLTTKR78 VFWKGVLEEL 88 LWFIKGSTNA98 KELSSKGVKI108 WDANGSRDFL118 DSLGFSTREE128 GDLGPVYGFQ 138 WRHFGAEYRD148 MESDYSGQGV158 DQLQRVIDTI168 KTNPDDCRII178 MAWNPRDLPL 189 MALPPHALQF201 YVVNSELSCQ211 LYQRSGDMGL221 GVPFNIASYA231 LLTYMIAHIT 241 GLKPGDFIHT251 LGDAHIYLNH261 IEPLKIQLQR271 EPRPFPKLRI281 LRKVEKIDDF 291 KAEDFQIEGY301 NPHPTIKMEM311 A> Chain D EPRPPHGELQ 32 YLGQIQHILR42 GVRKDDRTGT53 GTLSVFGMQA63 RYSLRDEFPL73 LTTKRVFWKG 83 VLEELLWFIK93 GSTNAKELSS103 KGVKIWDANG113 SRDFLDSLGF123 STREEGDLGP 133 VYGFQWRHFG143 AEYRDMESDY153 SGQGVDQLQR163 VIDTIKTNPD173 DCRIIMCAWN 183 PRDLPLMALP193 PHALQFYVVN205 SELSCQLYQR215 SGDMGLGVPF225 NIASYALLTY 235 MIAHITGLKP245 GDFIHTLGDA255 HIYLNHIEPL265 KIQLQREPRP275 FPKLRILRKV 285 EKIDDFKAED295 FQIEGYNPHP305 TIKMEMA
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .A:135 or .A:139 or .A:177 or .A:178 or .A:179 or .A:181 or .A:196 or .A:197 or .A:198 or .A:200 or .A:201 or .A:210 or .A:211 or .A:212 or .A:213 or .A:230 or .A:233 or .B:135 or .B:139 or .B:177 or .B:178 or .B:179 or .B:181 or .B:196 or .B:197 or .B:198 or .B:200 or .B:201 or .B:210 or .B:211 or .B:212 or .B:230 or .B:233 or .C:135 or .C:138 or .C:139 or .C:142 or .C:160 or .C:177 or .C:178 or .C:179 or .C:181 or .C:182 or .C:196 or .C:197 or .C:198 or .C:200 or .C:201 or .C:210 or .C:211 or .C:212 or .C:213 or .C:230 or .C:233 or .D:180 or .D:181 or .D:182 or .D:184 or .D:197 or .D:198 or .D:135 or .D:139 or .D:177 or .D:178 or .D:179 or .D:180 or .D:181 or .D:196 or .D:197 or .D:198 or .D:200 or .D:201 or .D:210 or .D:211 or .D:212 or .D:230 or .D:233; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR135[A]
3.528
TRP139[A]
3.074
ILE177[A]
3.931
ILE178[A]
3.221
MET179[A]
2.866
ALA181[A]
3.735
HIS196[A]
3.795
ALA197[A]
4.460
LEU198[A]
1.350
GLN200[A]
1.343
PHE201[A]
3.808
CYS210[A]
4.456
GLN211[A]
3.411
LEU212[A]
4.058
TYR213[A]
4.956
TYR230[A]
2.755
LEU233[A]
4.819
TYR135[B]
3.420
TRP139[B]
2.909
ILE177[B]
3.829
ILE178[B]
3.250
MET179[B]
2.889
ALA181[B]
3.815
HIS196[B]
3.792
ALA197[B]
4.701
LEU198[B]
1.353
GLN200[B]
1.334
PHE201[B]
3.813
CYS210[B]
4.157
GLN211[B]
3.291
LEU212[B]
4.005
TYR230[B]
2.618
LEU233[B]
4.780
TYR135[C]
3.550
GLN138[C]
3.950
TRP139[C]
3.075
PHE142[C]
3.967
GLN160[C]
2.670
ILE177[C]
4.008
ILE178[C]
3.228
MET179[C]
1.322
ALA181[C]
1.340
TRP182[C]
3.637
HIS196[C]
3.728
ALA197[C]
3.860
LEU198[C]
1.333
GLN200[C]
1.336
PHE201[C]
3.829
CYS210[C]
4.408
GLN211[C]
3.350
LEU212[C]
4.137
TYR213[C]
4.979
TYR230[C]
2.939
LEU233[C]
4.668
CYS180[D]
2.602
ALA181[D]
4.342
TRP182[D]
2.994
PRO184[D]
4.241
ALA197[D]
3.386
LEU198[D]
4.420
TYR135[D]
3.799
TRP139[D]
3.063
ILE177[D]
3.844
ILE178[D]
3.219
MET179[D]
2.904
CYS180[D]
4.418
ALA181[D]
3.519
HIS196[D]
3.947
ALA197[D]
4.472
LEU198[D]
1.340
GLN200[D]
1.324
PHE201[D]
3.767
CYS210[D]
4.188
GLN211[D]
3.307
LEU212[D]
3.863
TYR230[D]
2.515
LEU233[D]
4.809
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| PDB ID: 4E28 Structure of human thymidylate synthase in inactive conformation with a novel non-peptidic inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [6] |
| PDB Sequence |
PPHGELQYLG
35 QIQHILRCGV45 RKDDRTGTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKD130 LGPVYGFQWR140 HFYSGQGVDQ160 LQRVIDTIKT 170 NPDDRRIIMA181 WNPRDLPLMA191 LPPHALCQFY202 VVNSELSCQL212 YQRSGDMGLG 222 VPFNIASYAL232 LTYMIAHITG242 LKPGDFIHTL252 GDAHIYLNHI262 EPLKIQLQRE 272 PRPFPKLRIL282 RKVEKIDDFK292 AEDFQIEGYN302 PHPTIKMEM
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .A:138 or .A:139 or .A:160 or .A:163 or .A:178 or .A:179 or .A:181 or .A:182 or .A:193 or .A:194 or .A:196 or .A:197 or .A:198 or .A:199 or .A:215; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| PDB ID: 6R2E Crystal structure of the human thymidylate synthase (hTS) interface variant Q62R | ||||||
| Method | X-ray diffraction | Resolution | 2.55 Å | Mutation | Yes | [7] |
| PDB Sequence |
> Chain A
PPHGELQYLG 35 QIQHILRGVR46 KDDRTGTGTL56 SVFGMRARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSSKGV106 KIWDANGSRD116 FLDSLGFSTR126 EEGDLGPVYG 136 FQWRHFGAEY146 RDMESDYSGQ156 GVDQLQRVID166 TIKTNPDDRR176 IIMCAWNPRD 186 LPLMALPPHA197 LCQFYVVNSE207 LSCQLYQRSG217 DMGLGVPFNI227 ASYALLTYMI 237 AHITGLKPGD247 FIHTLGDAHI257 YLNHIEPLKI267 QLQREPRPFP277 KLRILRKVEK 287 IDDFKAEDFQ297 IEGYNPHPTI307 KMEMAV> Chain E PPHGELQYLG 35 QIQHILRGVR46 KDDRTGTGTL56 SVFGMRARYS66 LRDEFPLLTT76 KRVFWKGVLE 86 ELLWFIKGST96 NAKELSSKGV106 KIWDANGSRD116 FLDSLGFSTR126 EEGDLGPVYG 136 FQWRHFGAEY146 RDMESDYSGQ156 GVDQLQRVID166 TIKTNPDDRR176 IIMCAWNPRD 186 LPLMALPPHA197 LCQFYVVNSE207 LSCQLYQRSG217 DMGLGVPFNI227 ASYALLTYMI 237 AHITGLKPGD247 FIHTLGDAHI257 YLNHIEPLKI267 QLQREPRPFP277 KLRILRKVEK 287 IDDFKAEDFQ297 IEGYNPHPTI307 KMEMAV
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .A:38 or .A:39 or .A:40 or .A:41 or .A:42 or .A:44 or .A:45 or .A:50 or .A:57 or .A:58 or .A:135 or .A:192 or .A:193 or .A:194 or .A:196 or .A:197 or .A:213 or .A:214 or .A:215 or .A:216 or .A:217 or .A:218 or .A:256 or .A:258 or .E:41 or .E:46 or .E:56 or .E:259 or .E:262 or .E:266 or .E:50 or .E:135 or .E:192 or .E:193 or .E:194 or .E:196 or .E:197 or .E:213 or .E:214 or .E:215 or .E:216 or .E:217 or .E:218 or .E:256 or .E:258; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLN38[A]
4.884
HIS39[A]
2.903
ILE40[A]
3.652
LEU41[A]
3.711
ARG42[A]
1.346
GLY44[A]
1.328
VAL45[A]
3.585
ARG50[A]
4.229
SER57[A]
4.975
VAL58[A]
4.647
TYR135[A]
2.921
LEU192[A]
4.085
PRO193[A]
3.214
PRO194[A]
1.329
HIS196[A]
1.352
ALA197[A]
3.515
TYR213[A]
4.482
GLN214[A]
3.478
ARG215[A]
2.885
SER216[A]
3.232
GLY217[A]
4.844
ASP218[A]
3.592
HIS256[A]
2.976
TYR258[A]
2.721
LEU41[E]
3.791
ARG46[E]
3.809
LEU56[E]
3.762
LEU259[E]
4.664
ILE262[E]
3.499
LYS266[E]
3.281
ARG50[E]
4.986
TYR135[E]
2.721
LEU192[E]
3.751
PRO193[E]
3.197
PRO194[E]
1.315
HIS196[E]
1.339
ALA197[E]
3.498
TYR213[E]
4.365
GLN214[E]
3.487
ARG215[E]
2.970
SER216[E]
3.362
GLY217[E]
4.535
ASP218[E]
3.115
HIS256[E]
3.041
TYR258[E]
2.722
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| 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 | [8] |
| PDB Sequence |
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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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .F:135 or .F:139 or .F:177 or .F:178 or .F:179 or .F:180 or .F:181 or .F:196 or .F:197 or .F:198 or .F:200 or .F:201 or .F:210 or .F:211 or .F:212 or .F:213 or .F:230; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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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 | [9] |
| 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
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CME or .CME2 or .CME3 or :3CME;style chemicals stick;color identity;select .A:38 or .A:39 or .A:40 or .A:41 or .A:42 or .A:44 or .A:45 or .A:57 or .A:58; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Oxidation of Cysteine 195 of Huyman Thymidylate Synthase by Purpurogallin | ||||
| REF 2 | Oxidation of Cysteine 195 of Huyman Thymidylate Synthase by Purpurogallin | ||||
| REF 3 | Oxidation of Cysteine 195 of Huyman Thymidylate Synthase by Purpurogallin | ||||
| REF 4 | Cooperative inhibition of human thymidylate synthase by mixtures of active site binding and allosteric inhibitors. Biochemistry. 2007 Mar 13;46(10):2823-30. | ||||
| REF 5 | Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors. Molecules. 2019 Apr 7;24(7):1362. | ||||
| REF 6 | Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase. J Med Chem. 2012 Nov 26;55(22):10272-6. | ||||
| REF 7 | Evidence of Destabilization of the Human Thymidylate Synthase (hTS) Dimeric Structure Induced by the Interface Mutation Q62R. Biomolecules. 2019 Apr 3;9(4):134. | ||||
| REF 8 | 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 9 | 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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