Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T33641 | Target Info | |||
| Target Name | Cholesterol 24-hydroxylase (CYP46A1) | ||||
| Synonyms | Cytochrome P450 46A1; CYP46; Cholesterol 24S-hydroxylase; Cholesterol 24-monooxygenase; CH24H | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | CYP46A1 | ||||
| Biochemical Class | Paired donor oxygen oxidoreductase | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Tranylcypromine | Ligand Info | |||||
| Structure Description | Tranylcypromine complex of Cytochrome P450 46A1 | PDB:3MDR | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [1] |
| PDB Sequence |
RVLQDVFLDW
67 AKKYGPVVRV77 NVFHKTSVIV87 TSPESVKKFL97 MSTKYNKDSK107 MYRALQTVFG 117 ERLFGQGLVS127 ECNYERWHKQ137 RRVIDLAFSR147 SSLVSLMETF157 NEKAEQLVEI 167 LEAKADGQTP177 VSMQDMLTYT187 AMDILAKAAF197 GMETSMLLGA207 QKPLSQAVKL 217 MLEGITASRN227 TKRKQLREVR244 ESIRFLRQVG254 RDWVQRRREA264 LKRGEEVPAD 274 ILTQILKAEE284 GAQDDEGLLD294 NFVTFFIAGH304 ETSANHLAFT314 VMELSRQPEI 324 VARLQAEVDE334 VIGSKRYLDF344 EDLGRLQYLS354 QVLKESLRLY364 PPAWGTFRLL 374 EEETLIDGVR384 VPGNTPLLFS394 TYVMGRMDTY404 FEDPLTFNPD414 RFGPGAPKPR 424 FTYFPFSLGH434 RSCIGQQFAQ444 MEVKVVMAKL454 LQRLEFRLVP464 GQRFGLQEQA 474 TLKPLDPVLC484 TLRPRGW
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| Ligand Name: Voriconazole | Ligand Info | |||||
| Structure Description | Voriconazole complex of Cytochrome P450 46A1 | PDB:3MDT | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [1] |
| PDB Sequence |
VLQDVFLDWA
68 KKYGPVVRVN78 VFHKTSVIVT88 SPESVKKFLM98 STKYNKDSKM108 YRALQTVFGE 118 RLFGQGLVSE128 CNYERWHKQR138 RVIDLAFSRS148 SLVSLMETFN158 EKAEQLVEIL 168 EAKADGQTPV178 SMQDMLTYTA188 MDILAKAAFG198 METSMLLGAQ208 KPLSQAVKLM 218 LEGITASRNT228 KRKQLREVRE245 SIRFLRQVGR255 DWVQRRREAL265 KRGEEVPADI 275 LTQILKAEEG285 AQDDEGLLDN295 FVTFFIAGHE305 TSANHLAFTV315 MELSRQPEIV 325 ARLQAEVDEV335 IGSKRYLDFE345 DLGRLQYLSQ355 VLKESLRLYP365 PAWGTFRLLE 375 EETLIDGVRV385 PGNTPLLFST395 YVMGRMDTYF405 EDPLTFNPDR415 FGPGAPKPRF 425 TYFPFSLGHR435 SCIGQQFAQM445 EVKVVMAKLL455 QRLEFRLVPG465 QRFGLQEQAT 475 LKPLDPVLCT485 LRPR
|
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| Ligand Name: Clotrimazole | Ligand Info | |||||
| Structure Description | Clotrimazole complex of Cytochrome P450 46A1 | PDB:3MDV | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [1] |
| PDB Sequence |
VLQDVFLDWA
68 KKYGPVVRVN78 VFHKTSVIVT88 SPESVKKFLM98 STKYNKDSKM108 YRALQTVFGE 118 RLFGQGLVSE128 CNYERWHKQR138 RVIDLAFSRS148 SLVSLMETFN158 EKAEQLVEIL 168 EAKADGQTPV178 SMQDMLTYTA188 MDILAKAAFG198 METSMLLGAQ208 KPLSQAVKLM 218 LEGITASRNT228 KRKQLREVRE245 SIRFLRQVGR255 DWVQRRREAL265 KRGEEVPADI 275 LTQILKAEEG285 AQDDEGLLDN295 FVTFFIAGHE305 TSANHLAFTV315 MELSRQPEIV 325 ARLQAEVDEV335 IGSKRYLDFE345 DLGRLQYLSQ355 VLKESLRLYP365 PAWGTFRLLE 375 EETLIDGVRV385 PGNTPLLFST395 YVMGRMDTYF405 EDPLTFNPDR415 FGPGAPKPRF 425 TYFPFSLGHR435 SCIGQQFAQM445 EVKVVMAKLL455 QRLEFRLVPG465 QRFGLQEQAT 475 LKPLDPVLCT485 LRPR
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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 .CL6 or .CL62 or .CL63 or :3CL6;style chemicals stick;color identity;select .A:109 or .A:112 or .A:121 or .A:126 or .A:127 or .A:219 or .A:222 or .A:226 or .A:298 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: Fluvoxamine | Ligand Info | |||||
| Structure Description | Crystal Structure of Human Cytochrome P450 CYP46A1 with Fluvoxamine Bound | PDB:4ENH | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [2] |
| PDB Sequence |
VLQDVFLDWA
68 KKYGPVVRVN78 VFHKTSVIVT88 SPESVKKFLM98 STKYNKDSKM108 YRALQTVFGE 118 RLFGQGLVSE128 CNYERWHKQR138 RVIDLAFSRS148 SLVSLMETFN158 EKAEQLVEIL 168 EAKADGQTPV178 SMQDMLTYTA188 MDILAKAAFG198 METSMLLGAQ208 KPLSQAVKLM 218 LEGITASRNT228 LKRKQLREVR244 ESIRFLRQVG254 RDWVQRRREA264 LKRGEEVPAD 274 ILTQILKAEE284 GAQDDEGLLD294 NFVTFFIAGH304 ETSANHLAFT314 VMELSRQPEI 324 VARLQAEVDE334 VIGSKRYLDF344 EDLGRLQYLS354 QVLKESLRLY364 PPAWGTFRLL 374 EEETLIDGVR384 VPGNTPLLFS394 TYVMGRMDTY404 FEDPLTFNPD414 RFGPGAPKPR 424 FTYFPFSLGH434 RSCIGQQFAQ444 MEVKVVMAKL454 LQRLEFRLVP464 GQRFGLQEQA 474 TLKPLDPVLC484 TLRPRG
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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 .FVX or .FVX2 or .FVX3 or :3FVX;style chemicals stick;color identity;select .A:80 or .A:109 or .A:112 or .A:121 or .A:126 or .A:219 or .A:222 or .A:226 or .A:301 or .A:302 or .A:303 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:437 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PHE80
3.225
TYR109
4.127
LEU112
4.068
PHE121
3.688
VAL126
4.825
LEU219
3.705
ILE222
3.490
ARG226
4.042
ILE301
3.698
ALA302
2.825
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| Ligand Name: Posaconazole | Ligand Info | |||||
| Structure Description | Crystal Structure of Human Cytochrome P450 CYP46A1 with Posaconazole Bound | PDB:4J14 | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [3] |
| PDB Sequence |
GGRVLQDVFL
65 DWAKKYGPVV75 RVNVFHKTSV85 IVTSPESVKK95 FLMSTKYNKD105 SKMYRALQTV 115 FGERLFGQGL125 VSECNYERWH135 KQRRVIDLAF145 SRSSLVSLME155 TFNEKAEQLV 165 EILEAKADGQ175 TPVSMQDMLT185 YTAMDILAKA195 AFGMETSMLL205 GAQKPLSQAV 215 KLMLEGITAS225 RNTLAKFLPG235 KRKQLREVRE245 SIRFLRQVGR255 DWVQRRREAL 265 KRGEEVPADI275 LTQILKAEEG285 AQDDEGLLDN295 FVTFFIAGHE305 TSANHLAFTV 315 MELSRQPEIV325 ARLQAEVDEV335 IGSKRYLDFE345 DLGRLQYLSQ355 VLKESLRLYP 365 PAWGTFRLLE375 EETLIDGVRV385 PGNTPLLFST395 YVMGRMDTYF405 EDPLTFNPDR 415 FGPGAPKPRF425 TYFPFSLGHR435 SCIGQQFAQM445 EVKVVMAKLL455 QRLEFRLVPG 465 QRFGLQEQAT475 LKPLDPVLCT485 LRPRGW
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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 .X2N or .X2N2 or .X2N3 or :3X2N;style chemicals stick;color identity;select .A:79 or .A:80 or .A:81 or .A:108 or .A:109 or .A:111 or .A:112 or .A:121 or .A:126 or .A:226 or .A:227 or .A:228 or .A:229 or .A:297 or .A:298 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:371 or .A:437 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
VAL79
3.517
PHE80
3.421
HIS81
3.826
MET108
3.418
TYR109
4.097
ALA111
3.588
LEU112
3.873
PHE121
3.046
VAL126
3.752
ARG226
3.081
ASN227
4.042
THR228
4.848
LEU229
4.353
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| Ligand Name: TAK-935 | Ligand Info | |||||
| Structure Description | Co-complex CYP46A1 with 7742 (Soticlestat/TAK-935)) | PDB:7LRL | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [4] |
| PDB Sequence |
SRYEHIPGPP
37 GRVLQDVFLD66 WAKKYGPVVR76 VNVFHKTSVI86 VTSPESVKKF96 LMSTKYNKDS 106 KMYRALQTVF116 GERLFGQGLV126 SECNYERWHK136 QRRVIDLAFS146 RSSLVSLMET 156 FNEKAEQLVE166 ILEAKADGQT176 PVSMQDMLTY186 TAMDILAKAA196 FGMETSMLLG 206 AQKPLSQAVK216 LMLEGITASR226 KRKQLREVRE245 SIRFLRQVGR255 DWVQRRREAL 265 KRGEEVPADI275 LTQILKAEEG285 AQDDEGLLDN295 FVTFFIAGHE305 TSANHLAFTV 315 MELSRQPEIV325 ARLQAEVDEV335 IGSKRYLDFE345 DLGRLQYLSQ355 VLKESLRLYP 365 PAWGTFRLLE375 EETLIDGVRV385 PGNTPLLFST395 YVMGRMDTYF405 EDPLTFNPDR 415 FGPGAPKPRF425 TYFPFSLGHR435 SCIGQQFAQM445 EVKVVMAKLL455 QRLEFRLVPG 465 QRFGLQEQAT475 LKPLDPVLCT485 LRPRGW
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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 .YBS or .YBS2 or .YBS3 or :3YBS;style chemicals stick;color identity;select .A:108 or .A:109 or .A:111 or .A:112 or .A:121 or .A:126 or .A:219 or .A:222 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:371 or .A:437 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: Thioperamide | Ligand Info | |||||
| Structure Description | Thioperamide complex of Cytochrome P450 46A1 | PDB:3MDM | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [1] |
| PDB Sequence |
GRVLQDVFLD
66 WAKKYGPVVR76 VNVFHKTSVI86 VTSPESVKKF96 LMSTKYNKDS106 KMYRALQTVF 116 GERLFGQGLV126 SECNYERWHK136 QRRVIDLAFS146 RSSLVSLMET156 FNEKAEQLVE 166 ILEAKADGQT176 PVSMQDMLTY186 TAMDILAKAA196 FGMETSMLLG206 AQKPLSQAVK 216 LMLEGITASR226 NTLAKFLPGK236 RKQLREVRES246 IRFLRQVGRD256 WVQRRREALK 266 RGEEVPADIL276 TQILKAEEGA286 QDDEGLLDNF296 VTFFIAGHET306 SANHLAFTVM 316 ELSRQPEIVA326 RLQAEVDEVI336 GSKRYLDFED346 LGRLQYLSQV356 LKESLRLYPP 366 AWGTFRLLEE376 ETLIDGVRVP386 GNTPLLFSTY396 VMGRMDTYFE406 DPLTFNPDRF 416 GPGAPKPRFT426 YFPFSLGHRS436 CIGQQFAQME446 VKVVMAKLLQ456 RLEFRLVPGQ 466 RFGLQEQATL476 KPLDPVLCTL486 RPRGW
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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 .FJZ or .FJZ2 or .FJZ3 or :3FJZ;style chemicals stick;color identity;select .A:80 or .A:108 or .A:109 or .A:112 or .A:121 or .A:126 or .A:222 or .A:226 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:437 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: (3-Fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone | Ligand Info | |||||
| Structure Description | Co-complex CYP46A1 with compound 3f | PDB:7N6F | ||||
| Method | X-ray diffraction | Resolution | 1.40 Å | Mutation | No | [5] |
| PDB Sequence |
HSRYEHIPGP
36 PGRVLQDVFL65 DWAKKYGPVV75 RVNVFHKTSV85 IVTSPESVKK95 FLMSTKYNKD 105 SKMYRALQTV115 FGERLFGQGL125 VSECNYERWH135 KQRRVIDLAF145 SRSSLVSLME 155 TFNEKAEQLV165 EILEAKADGQ175 TPVSMQDMLT185 YTAMDILAKA195 AFGMETSMLL 205 GAQKPLSQAV215 KLMLEGITAS225 RNKRKQLREV243 RESIRFLRQV253 GRDWVQRRRE 263 ALKRGEEVPA273 DILTQILKAE283 EGAQDDEGLL293 DNFVTFFIAG303 HETSANHLAF 313 TVMELSRQPE323 IVARLQAEVD333 EVIGSKRYLD343 FEDLGRLQYL353 SQVLKESLRL 363 YPPAWGTFRL373 LEEETLIDGV383 RVPGNTPLLF393 STYVMGRMDT403 YFEDPLTFNP 413 DRFGPGAPKP423 RFTYFPFSLG433 HRSCIGQQFA443 QMEVKVVMAK453 LLQRLEFRLV 463 PGQRFGLQEQ473 ATLKPLDPVL483 CTLRPR
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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 .0I1 or .0I12 or .0I13 or :30I1;style chemicals stick;color identity;select .A:80 or .A:108 or .A:109 or .A:112 or .A:121 or .A:126 or .A:218 or .A:219 or .A:222 or .A:226 or .A:301 or .A:302 or .A:303 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:437 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PHE80
3.964
MET108
3.783
TYR109
3.271
LEU112
3.537
PHE121
3.538
VAL126
3.756
MET218
4.519
LEU219
3.183
ILE222
3.485
ARG226
2.948
ILE301
3.483
ALA302
3.123
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| Ligand Name: N-cyclopropyl-1-(4-phenylpyridin-3-yl)piperidine-4-carboxamide | Ligand Info | |||||
| Structure Description | Co-complex CYP46A1 with 0420 (compound 6) | PDB:7N3L | ||||
| Method | X-ray diffraction | Resolution | 1.63 Å | Mutation | No | [6] |
| PDB Sequence |
SRYEHIPGPP
37 GRVLQDVFLD66 WAKKYGPVVR76 VNVFHKTSVI86 VTSPESVKKF96 LMSTKYNKDS 106 KMYRALQTVF116 GERLFGQGLV126 SECNYERWHK136 QRRVIDLAFS146 RSSLVSLMET 156 FNEKAEQLVE166 ILEAKADGQT176 PVSMQDMLTY186 TAMDILAKAA196 FGMETSMLLG 206 AQKPLSQAVK216 LMLEGITASR226 KRKQLREVRE245 SIRFLRQVGR255 DWVQRRREAL 265 KRGEEVPADI275 LTQILKAEEG285 AQDDEGLLDN295 FVTFFIAGHE305 TSANHLAFTV 315 MELSRQPEIV325 ARLQAEVDEV335 IGSKRYLDFE345 DLGRLQYLSQ355 VLKESLRLYP 365 PAWGTFRLLE375 EETLIDGVRV385 PGNTPLLFST395 YVMGRMDTYF405 EDPLTFNPDR 415 FGPGAPKPRF425 TYFPFSLGHR435 SCIGQQFAQM445 EVKVVMAKLL455 QRLEFRLVPG 465 QRFGLQEQAT475 LKPLDPVLCT485 LRPR
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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 .04Y or .04Y2 or .04Y3 or :304Y;style chemicals stick;color identity;select .A:80 or .A:108 or .A:109 or .A:112 or .A:121 or .A:126 or .A:219 or .A:222 or .A:226 or .A:301 or .A:302 or .A:303 or .A:305 or .A:306 or .A:367 or .A:371 or .A:437 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: [5,5-dimethyl-3-(2-methylphenyl)-4H-pyrazol-1-yl]-pyridin-4-ylmethanone | Ligand Info | |||||
| Structure Description | Co-complex CYP46A1 with 9129 (1b) | PDB:7LS4 | ||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [4] |
| PDB Sequence |
SRYEHIPGPP
37 VLQDVFLDWA68 KKYGPVVRVN78 VFHKTSVIVT88 SPESVKKFLM98 STKYNKDSKM 108 YRALQTVFGE118 RLFGQGLVSE128 CNYERWHKQR138 RVIDLAFSRS148 SLVSLMETFN 158 EKAEQLVEIL168 EAKADGQTPV178 SMQDMLTYTA188 MDILAKAAFG198 METSMLLGAQ 208 KPLSQAVKLM218 LEGITASRKR237 KQLREVRESI247 RFLRQVGRDW257 VQRRREALKR 267 GEEVPADILT277 QILKAEEGAQ287 DDEGLLDNFV297 TFFIAGHETS307 ANHLAFTVME 317 LSRQPEIVAR327 LQAEVDEVIG337 SKRYLDFEDL347 GRLQYLSQVL357 KESLRLYPPA 367 WGTFRLLEEE377 TLIDGVRVPG387 NTPLLFSTYV397 MGRMDTYFED407 PLTFNPDRFG 417 PGAPKPRFTY427 FPFSLGHRSC437 IGQQFAQMEV447 KVVMAKLLQR457 LEFRLVPGQR 467 FGLQEQATLK477 PLDPVLCTLR487 PR
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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 .YCG or .YCG2 or .YCG3 or :3YCG;style chemicals stick;color identity;select .A:112 or .A:121 or .A:126 or .A:219 or .A:222 or .A:301 or .A:302 or .A:305 or .A:306 or .A:366 or .A:367 or .A:368 or .A:369 or .A:437 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| Ligand Name: (4-Benzyl-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone | Ligand Info | |||||
| Structure Description | Co-complex CYP46A1 with 8114 (3f) | PDB:7LS3 | ||||
| Method | X-ray diffraction | Resolution | 2.15 Å | Mutation | No | [4] |
| PDB Sequence |
SRYEHIPGPP
37 VLQDVFLDWA68 KKYGPVVRVN78 VFKTSVIVTS89 PESVKKFLMS99 TKYNKDSKMY 109 RALQTVFGER119 LFGQGLVSEC129 NYERWHKQRR139 VIDLAFSRSS149 LVSLMETFNE 159 KAEQLVEILE169 AKADGQTPVS179 MQDMLTYTAM189 DILAKAAFGM199 ETSMLLGAQK 209 PLSQAVKLML219 EGITAKRKQL240 REVRESIRFL250 RQVGRDWVQR260 RREALKRGEE 270 VPADILTQIL280 KAEEGAQDDE290 GLLDNFVTFF300 IAGHETSANH310 LAFTVMELSR 320 QPEIVARLQA330 EVDEVIGSKR340 YLDFEDLGRL350 QYLSQVLKES360 LRLYPPAWGT 370 FRLLEEETLI380 DGVRVPGNTP390 LLFSTYVMGR400 MDTYFEDPLT410 FNPDRFGPGA 420 PKPRFTYFPF430 SLGHRSCIGQ440 QFAQMEVKVV450 MAKLLQRLEF460 RLVPGQRFGL 470 QEQATLKPLD480 PVLCTLRPR
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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 .YCJ or .YCJ2 or .YCJ3 or :3YCJ;style chemicals stick;color identity;select .A:80 or .A:108 or .A:109 or .A:112 or .A:121 or .A:126 or .A:219 or .A:222 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:437 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PHE80
4.114
MET108
3.678
TYR109
3.978
LEU112
3.636
PHE121
3.581
VAL126
3.304
LEU219
3.801
ILE222
3.687
ILE301
3.610
ALA302
3.417
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|||||
| Ligand Name: Cholesterol sulfate | Ligand Info | |||||
| Structure Description | Crystal structure of human cytochrome P450 46A1 in complex with cholesterol-3-sulphate | PDB:2Q9F | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [7] |
| PDB Sequence |
VLQDVFLDWA
68 KKYGPVVRVN78 VFHKTSVIVT88 SPESVKKFLM98 STKYNKDSKM108 YRALQTVFGE 118 RLFGQGLVSE128 CNYERWHKQR138 RVIDLAFSRS148 SLVSLMETFN158 EKAEQLVEIL 168 EAKADGQTPV178 SMQDMLTYTA188 MDILAKAAFG198 METSMLLGAQ208 KPLSQAVKLM 218 LEGITASRNT228 LAKFLPGKRK238 QLREVRESIR248 FLRQVGRDWV258 QRRREALKRG 268 EEVPADILTQ278 ILKAEEGAQD288 DEGLLDNFVT298 FFIAGHETSA308 NHLAFTVMEL 318 SRQPEIVARL328 QAEVDEVIGS338 KRYLDFEDLG348 RLQYLSQVLK358 ESLRLYPPAW 368 GTFRLLEEET378 LIDGVRVPGN388 TPLLFSTYVM398 GRMDTYFEDP408 LTFNPDRFGP 418 GAPKPRFTYF428 PFSLGHRSCI438 GQQFAQMEVK448 VVMAKLLQRL458 EFRLVPGQRF 468 GLQEQATLKP478 LDPVLCTLRP488 RGW
|
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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 .C3S or .C3S2 or .C3S3 or :3C3S;style chemicals stick;color identity;select .A:79 or .A:80 or .A:81 or .A:82 or .A:108 or .A:109 or .A:110 or .A:111 or .A:112 or .A:121 or .A:126 or .A:222 or .A:223 or .A:225 or .A:226 or .A:227 or .A:301 or .A:302 or .A:306 or .A:366 or .A:367 or .A:368 or .A:369 or .A:371 or .A:472 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
VAL79
4.831
PHE80
3.370
HIS81
2.961
LYS82
4.972
MET108
3.421
TYR109
3.665
ARG110
2.461
ALA111
3.986
LEU112
4.252
PHE121
3.817
VAL126
3.702
ILE222
3.896
THR223
4.841
SER225
3.850
|
|||||
| Ligand Name: (R)-Bicalutamide | Ligand Info | |||||
| Structure Description | Crystal Structure of Human CYP46A1 P450 with bicalutamide Bound | PDB:4FIA | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [8] |
| PDB Sequence |
GRVLQDVFLD
66 WAKKYGPVVR76 VNVFHKTSVI86 VTSPESVKKF96 LMSTKYNKDS106 KMYRALQTVF 116 GERLFGQGLV126 SECNYERWHK136 QRRVIDLAFS146 RSSLVSLMET156 FNEKAEQLVE 166 ILEAKADGQT176 PVSMQDMLTY186 TAMDILAKAA196 FGMETSMLLG206 AQKPLSQAVK 216 LMLEGITASR226 NTKRKQLREV243 RESIRFLRQV253 GRDWVQRRRE263 ALKRGEEVPA 273 DILTQILKAE283 EGAQDDEGLL293 DNFVTFFIAG303 HETSANHLAF313 TVMELSRQPE 323 IVARLQAEVD333 EVIGSKRYLD343 FEDLGRLQYL353 SQVLKESLRL363 YPPAWGTFRL 373 LEEETLIDGV383 RVPGNTPLLF393 STYVMGRMDT403 YFEDPLTFNP413 DRFGPGAPKP 423 RFTYFPFSLG433 HRSCIGQQFA443 QMEVKVVMAK453 LLQRLEFRLV463 PGQRFGLQEQ 473 ATLKPLDPVL483 CTLRPR
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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 .198 or .1982 or .1983 or :3198;style chemicals stick;color identity;select .A:79 or .A:80 or .A:108 or .A:109 or .A:111 or .A:112 or .A:121 or .A:126 or .A:222 or .A:226 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:472 or .A:473 or .A:474 or .A:475; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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VAL79
4.722
PHE80
3.031
MET108
4.451
TYR109
3.913
ALA111
4.304
LEU112
3.747
PHE121
3.725
VAL126
3.803
ILE222
3.542
ARG226
3.405
ILE301
3.863
ALA302
3.417
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| Ligand Name: (S)-Bicalutamide | Ligand Info | |||||
| Structure Description | Crystal Structure of Human CYP46A1 P450 with bicalutamide Bound | PDB:4FIA | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [8] |
| PDB Sequence |
GRVLQDVFLD
66 WAKKYGPVVR76 VNVFHKTSVI86 VTSPESVKKF96 LMSTKYNKDS106 KMYRALQTVF 116 GERLFGQGLV126 SECNYERWHK136 QRRVIDLAFS146 RSSLVSLMET156 FNEKAEQLVE 166 ILEAKADGQT176 PVSMQDMLTY186 TAMDILAKAA196 FGMETSMLLG206 AQKPLSQAVK 216 LMLEGITASR226 NTKRKQLREV243 RESIRFLRQV253 GRDWVQRRRE263 ALKRGEEVPA 273 DILTQILKAE283 EGAQDDEGLL293 DNFVTFFIAG303 HETSANHLAF313 TVMELSRQPE 323 IVARLQAEVD333 EVIGSKRYLD343 FEDLGRLQYL353 SQVLKESLRL363 YPPAWGTFRL 373 LEEETLIDGV383 RVPGNTPLLF393 STYVMGRMDT403 YFEDPLTFNP413 DRFGPGAPKP 423 RFTYFPFSLG433 HRSCIGQQFA443 QMEVKVVMAK453 LLQRLEFRLV463 PGQRFGLQEQ 473 ATLKPLDPVL483 CTLRPR
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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 .0U9 or .0U92 or .0U93 or :30U9;style chemicals stick;color identity;select .A:79 or .A:80 or .A:108 or .A:109 or .A:111 or .A:112 or .A:121 or .A:126 or .A:222 or .A:226 or .A:301 or .A:302 or .A:305 or .A:306 or .A:367 or .A:368 or .A:369 or .A:370 or .A:371 or .A:472 or .A:473 or .A:474 or .A:475; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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VAL79
4.716
PHE80
3.053
MET108
4.400
TYR109
3.964
ALA111
4.445
LEU112
3.645
PHE121
3.819
VAL126
3.880
ILE222
3.637
ARG226
3.433
ILE301
3.799
ALA302
3.423
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem. 2010 Oct 8;285(41):31783-95. | ||||
| REF 2 | In silico and intuitive predictions of CYP46A1 inhibition by marketed drugs with subsequent enzyme crystallization in complex with fluvoxamine. Mol Pharmacol. 2012 Nov;82(5):824-34. | ||||
| REF 3 | Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1. Mol Pharmacol. 2013 Jul;84(1):86-94. | ||||
| REF 4 | Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H). J Med Chem. 2021 Aug 26;64(16):12228-12244. | ||||
| REF 5 | Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H). doi:10.1016/j.ejmech.2022.114612. | ||||
| REF 6 | Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors. J Med Chem. 2022 Feb 24;65(4):3343-3358. | ||||
| REF 7 | Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9546-51. | ||||
| REF 8 | Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response. J Biol Chem. 2013 Feb 15;288(7):4613-24. | ||||
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