Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T99009 | Target Info | |||
| Target Name | HUMAN dihydroorotate dehydrogenase (DHODH) | ||||
| Synonyms | Dihydroorotate oxidase; Dihydroorotate dehydrogenase (quinone), mitochondrial; DHOdehase; DHODH | ||||
| Gene Name | DHODH | ||||
| Biochemical Class | CH-CH donor oxidoreductase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Decylamine-N,N-dimethyl-N-oxide | Ligand Info | |||
| Canonical SMILES | CCCCCCCCCC[N+](C)(C)[O-] | ||||
| InChI | 1S/C12H27NO/c1-4-5-6-7-8-9-10-11-12-13(2,3)14/h4-12H2,1-3H3 | ||||
| InChIKey | ZRKZFNZPJKEWPC-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 62452 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 3W7R Structure of Human dihydroorotate dehydrogenase in complex with mii-4-097 | ||||||
| Method | X-ray diffraction | Resolution | 1.68 Å | Mutation | No | [1] |
| PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 RARFQDSDML79 EVRVLGHKFR 89 NPVGIAAGFD99 KHGEAVDGLY109 KMGFGFVEIG119 SVTPKPQEGN129 PRPRVFRLPE 139 DQAVINRYGF149 NSHGLSVVEH159 RLRARQQKQA169 KLTEDGLPLG179 VNLGKNKTSV 189 DAAEDYAEGV199 RVLGPLADYL209 VVNVSSPNTA219 GLRSLQGKAE229 LRRLLTKVLQ 239 ERDGLRRVHR249 PAVLVKIAPD259 LTSQDKEDIA269 SVVKELGIDG279 LIVTNTTVSR 289 PAGLQGALRS299 ETGGLSGKPL309 RDLSTQTIRE319 MYALTQGRVP329 IIGVGGVSSG 339 QDALEKIRAG349 ASLVQLYTAL359 TFWGPPVVGK369 VKRELEALLK379 EQGFGGVTDA 389 IGADHRR
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GLY33
3.410
ARG36
3.762
PHE37
3.395
TYR38
3.963
GLU40
3.441
HIS41
2.977
LEU42
3.862
PRO44
3.729
THR45
3.653
LEU46
4.026
GLN47
3.321
GLY48
3.447
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| PDB ID: 6VND Quaternary Complex of human dihydroorotate dehydrogenase (DHODH) with flavin mononucleotide (FMN), orotic acid and AG-636 | ||||||
| Method | X-ray diffraction | Resolution | 1.97 Å | Mutation | No | [2] |
| PDB Sequence |
ATGDERFYAE
39 HLMPTLQGLL49 DPESAHRLAV59 RFTSLGLLPR69 ARFQDSDMLE79 VRVLGHKFRN 89 PVGIAAGFDK99 HGEAVDGLYK109 MGFGFVEIGS119 VTPKPQEGNP129 RPRVFRLPED 139 QAVINRYGFN149 SHGLSVVEHR159 LRARQQKQAK169 LTEDGLPLGV179 NLGKNKTSVD 189 AAEDYAEGVR199 VLGPLADYLV209 VNVSSPNTAG219 LRSLQGKAEL229 RRLLTKVLQE 239 RDGLRRVHRP249 AVLVKIAPDL259 TSQDKEDIAS269 VVKELGIDGL279 IVTNTTVSRP 289 AGLQGALRSE299 TGGLSGKPLR309 DLSTQTIREM319 YALTQGRVPI329 IGVGGVSSGQ 339 DALEKIRAGA349 SLVQLYTALT359 FWGPPVVGKV369 KRELEALLKE379 QGFGGVTDAI 389 GADHR
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| PDB ID: 1D3G HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH BREQUINAR ANALOG | ||||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [3] |
| PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 FQDSDMLEVR82 VLGHKFRNPV 92 GIAAGFDKHG102 EAVDGLYKMG112 FGFVEIGSVT122 PKPQEGNPRP132 RVFRLPEDQA 142 VINRYGFNSH152 GLSVVEHRLR162 ARQQKQAKLT172 EDGLPLGVNL182 GKNKTSVDAA 192 EDYAEGVRVL202 GPLADYLVVN212 VSSPNTAGLG226 KAELRRLLTK236 VLQERDGLRR 246 VHRPAVLVKI256 APDLTSQDKE266 DIASVVKELG276 IDGLIVTNTT286 VSRPAGLQGA 296 LRSETGGLSG306 KPLRDLSTQT316 IREMYALTQG326 RVPIIGVGGV336 SSGQDALEKI 346 RAGASLVQLY356 TALTFWGPPV366 VGKVKRELEA376 LLKEQGFGGV386 TDAIGADHRR 396
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| PDB ID: 6ET4 HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [4] |
| PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 RARFQDSDML79 EVRVLGHKFR 89 NPVGIAAGFD99 KHGEAVDGLY109 KMGFGFVEIG119 SVTPKPQEGN129 PRPRVFRLPE 139 DQAVINRYGF149 NSHGLSVVEH159 RLRARQQKQA169 KLTEDGLPLG179 VNLGKNKTSV 189 DAAEDYAEGV199 RVLGPLADYL209 VVNVSSPNTA219 GLRSLQGKAE229 LRRLLTKVLQ 239 ERDGLRRVHR249 PAVLVKIAPD259 LTSQDKEDIA269 SVVKELGIDG279 LIVTNTTVSR 289 PAGLQGALRS299 ETGGLSGKPL309 RDLSTQTIRE319 MYALTQGRVP329 IIGVGGVSSG 339 QDALEKIRAG349 ASLVQLYTAL359 TFWGPPVVGK369 VKRELEALLK379 EQGFGGVTDA 389 IGADHRR
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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 .DDQ or .DDQ2 or .DDQ3 or :3DDQ;style chemicals stick;color identity;select .A:38 or .A:42 or .A:46 or .A:58 or .A:62 or .A:67 or .A:68 or .A:69 or .A:70; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6GK0 HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH CLASS III HISTONE DEACETYLASE INHIBITOR | ||||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | No | [5] |
| PDB Sequence |
GDERFYAEHL
42 MPTLQGLLDP52 ESAHRLAVRF62 TSLGLLPRAR72 FQDSDMLEVR82 VLGHKFRNPV 92 GIAAGFDKHG102 EAVDGLYKMG112 FGFVEIGSVT122 PKPQEGNPRP132 RVFRLPEDQA 142 VINRYGFNSH152 GLSVVEHRLR162 ARQQKQAKLT172 EDGLPLGVNL182 GKNKTSVDAA 192 EDYAEGVRVL202 GPLADYLVVN212 VSSPNTAGLR222 SLQGKAELRR232 LLTKVLQERD 242 GLRRVHRPAV252 LVKIAPDLTS262 QDKEDIASVV272 KELGIDGLIV282 TNTTVSRPAG 292 LQGALRSETG302 GLSGKPLRDL312 STQTIREMYA322 LTQGRVPIIG332 VGGVSSGQDA 342 LEKIRAGASL352 VQLYTALTFW362 GPPVVGKVKR372 ELEALLKEQG382 FGGVTDAIGA 392 DHR
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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 .DDQ or .DDQ2 or .DDQ3 or :3DDQ;style chemicals stick;color identity;select .A:53 or .A:57 or .A:101 or .A:125 or .A:126 or .A:127 or .A:131 or .A:133 or .A:150 or .A:151 or .A:152 or .A:156 or .A:160; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2PRL The structures of apo- and inhibitor bound human dihydroorotate dehydrogenase reveal conformational flexibility within the inhibitor binding site | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [6] |
| PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 RARFQDSDML79 EVRVLGHKFR 89 NPVGIAAGFD99 KHGEAVDGLY109 KMGFGFVEIG119 SVTPKPQEGN129 PRPRVFRLPE 139 DQAVINRYGF149 NSHGLSVVEH159 RLRARQQKQA169 KLTEDGLPLG179 VNLGKNKTSV 189 DAAEDYAEGV199 RVLGPLADYL209 VVNVSSPNTA219 GLRSLQGKAE229 LRRLLTKVLQ 239 ERDGLRRVHR249 PAVLVKIAPD259 LTSQDKEDIA269 SVVKELGIDG279 LIVTNTTVSR 289 PAGLQGALRS299 ETGGLSGKPL309 RDLSTQTIRE319 MYALTQGRVP329 IIGVGGVSSG 339 QDALEKIRAG349 ASLVQLYTAL359 TFWGPPVVGK369 VKRELEALLK379 EQGFGGVTDA 389 IGADHRR
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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 .DDQ or .DDQ2 or .DDQ3 or :3DDQ;style chemicals stick;color identity;select .A:30 or .A:31 or .A:38 or .A:42 or .A:46 or .A:58 or .A:62 or .A:66 or .A:67 or .A:68 or .A:69 or .A:70; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2PRH The structures of apo- and inhibitor bound human dihydroorotate dehydrogenase reveal conformational flexibility within the inhibitor binding site | ||||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [6] |
| PDB Sequence |
MATGDERFYA
39 EHLMPTLQGL49 LDPESAHRLA59 VRFTSLGLLP69 RARFQDSDML79 EVRVLGHKFR 89 NPVGIAAGFD99 KHGEAVDGLY109 KMGFGFVEIG119 SVTPKPQEGN129 PRPRVFRLPE 139 DQAVINRYGF149 NSHGLSVVEH159 RLRARQQKQA169 KLTEDGLPLG179 VNLGKNKTSV 189 DAAEDYAEGV199 RVLGPLADYL209 VVNVSSPGKA228 ELRRLLTKVL238 QERDGLRRVH 248 RPAVLVKIAP258 DLTSQDKEDI268 ASVVKELGID278 GLIVTNTTVS288 RPAGLQGALR 298 SETGGLSGKP308 LRDLSTQTIR318 EMYALTQGRV328 PIIGVGGVSS338 GQDALEKIRA 348 GASLVQLYTA358 LTFWGPPVVG368 KVKRELEALL378 KEQGFGGVTD388 AIGADHRR |
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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 .DDQ or .DDQ2 or .DDQ3 or :3DDQ;style chemicals stick;color identity;select .A:30 or .A:31 or .A:32 or .A:38 or .A:42 or .A:46 or .A:58 or .A:59 or .A:62 or .A:67 or .A:68 or .A:69; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2WV8 Complex of human dihydroorotate dehydrogenase with the inhibitor 221290 | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [7] |
| PDB Sequence |
TGDERFYAEH
41 LMPTLQGLLD51 PESAHRLAVR61 FTSLGLLPRA71 RFQDSDMLEV81 RVLGHKFRNP 91 VGIAAGFDKH101 GEAVDGLYKM111 GFGFVEIGSV121 TPKPQEGNPR131 PRVFRLPEDQ 141 AVINRYGFNS151 HGLSVVEHRL161 RARQQKQAKL171 TEDGLPLGVN181 LGKNKTSVDA 191 AEDYAEGVRV201 LGPLADYLVV211 NVSSPNTAGL221 RSLQGKAELR231 RLLTKVLQER 241 DGLRRVHRPA251 VLVKIAPDLT261 SQDKEDIASV271 VKELGIDGLI281 VTNTTVSRPA 291 GLQGALRSET301 GGLSGKPLRD311 LSTQTIREMY321 ALTQGRVPII331 GVGGVSSGQD 341 ALEKIRAGAS351 LVQLYTALTF361 WGPPVVGKVK371 RELEALLKEQ381 GFGGVTDAIG 391 ADHRR
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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 .DDQ or .DDQ2 or .DDQ3 or :3DDQ;style chemicals stick;color identity;select .A:38 or .A:42 or .A:46 or .A:58 or .A:59 or .A:62 or .A:66 or .A:67 or .A:68 or .A:69 or .A:70; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structure of Human dihydroorotate dehydrogenase in complex with mii-4-097 | ||||
| REF 2 | Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase. Mol Cancer Ther. 2020 Dec;19(12):2502-2515. | ||||
| REF 3 | Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure. 2000 Jan 15;8(1):25-33. | ||||
| REF 4 | A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nat Commun. 2018 Mar 16;9(1):1107. | ||||
| REF 5 | Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology. J Biol Chem. 2020 Dec 25;295(52):17935-17949. | ||||
| REF 6 | The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites. Biochemistry. 2008 Aug 26;47(34):8929-36. | ||||
| REF 7 | Inhibition of human DHODH by 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids identified by structure-guided fragment selection. ChemMedChem. 2010 Apr 6;5(4):608-17. | ||||
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