Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T02506 | Target Info | |||
| Target Name | HUMAN estrogen receptor (ESR1) | ||||
| Synonyms | Nuclear receptor subfamily 3 group A member 1; NR3A1; Estradiol receptor; ESR; ER-alpha; ER | ||||
| Gene Name | ESR1 | ||||
| Biochemical Class | Nuclear hormone receptor | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Raloxifene | Ligand Info | |||
| Canonical SMILES | C1CCN(CC1)CCOC2=CC=C(C=C2)C(=O)C3=C(SC4=C3C=CC(=C4)O)C5=CC=C(C=C5)O | ||||
| InChI | 1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2 | ||||
| InChIKey | GZUITABIAKMVPG-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 5035 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7UJC Raloxifene in Complex with Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutation | ||||||
| Method | X-ray diffraction | Resolution | 1.78 Å | Mutation | Yes | [1] |
| PDB Sequence |
LALSLTADQM
315 VSALLDAEPP325 ILYSEYFSEA340 SMMGLLTNLA350 DRELVHMINW360 AKRVPGFVDL 370 TLHDQVHLLE380 SAWLEILMIG390 LVWRSMEHPG400 KLLFAPNLLL410 DRNQGKSVEG 420 MVEIFDMLLA430 TSSRFRMMNL440 QGEEFVCLKS450 IILLNSGVYT460 FTLKSLEEKD 473 HIHRVLDKIT483 DTLIHLMAKA493 GLTLQQQHQR503 LAQLLLILSH513 IRHMSNKGME 523 HLYSMLSDLL540 LEMLDAHRL
|
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|
|
MET343
4.156
LEU346
3.397
THR347
3.547
LEU349
4.168
ALA350
3.780
ASP351
2.806
GLU353
2.500
LEU354
3.578
TRP383
3.821
LEU384
4.137
LEU387
3.672
MET388
4.109
LEU391
3.866
|
|||||
| PDB ID: 7KBS Estrogen Receptor Alpha Ligand Binding Domain in Complex with Raloxifene | ||||||
| Method | X-ray diffraction | Resolution | 1.83 Å | Mutation | Yes | [1] |
| PDB Sequence |
ALSLTADQMV
316 SALLDAEPPI326 LYSEYDPTRP336 FSEASMMGLL346 TNLADRELVH356 MINWAKRVPG 366 FVDLTLHDQV376 HLLESAWLEI386 LMIGLVWRSM396 EHPGKLLFAP406 NLLLDRNQGK 416 SVEGMVEIFD426 MLLATSSRFR436 MMNLQGEEFV446 CLKSIILLNS456 GVYTFSTLKS 468 LEEKDHIHRV478 LDKITDTLIH488 LMAKAGLTLQ498 QQHQRLAQLL508 LILSHIRHMS 518 NKGMEHLYSM528 KSKNVVPSYD538 LLLEMLDAHR548 LH
|
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|
|
MET343
3.925
LEU346
3.450
THR347
3.680
LEU349
4.083
ALA350
3.612
ASP351
2.745
GLU353
2.397
LEU354
3.923
TRP383
3.764
LEU384
4.132
LEU387
3.646
MET388
3.918
LEU391
3.898
ARG394
3.129
|
|||||
| PDB ID: 2QXS Crystal Structure of Antagonizing Mutant 536S of the Estrogen Receptor Alpha Ligand Binding Domain Complexed to Raloxifene | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [2] |
| PDB Sequence |
LALSLTADQM
315 VSALLDAEPP325 ILYSEYDPRP336 FSASMMGLLT347 NLADRELVHM357 INWAKRVPGF 367 VDLTLHDQVH377 LLECAWLEIL387 MIGLVWRSME397 HPGKLLFAPN407 LLLDRNQGKC 417 VEGMVEIFDM427 LLATSSRFRM437 MNLQGEEFVC447 LKSIILLNSG457 VYTFTLKSLE 470 EKDHIHRVLD480 KITDTLIHLM490 AKAGLTLQQQ500 HQRLAQLLLI510 LSHIRHMSNK 520 GMEHLYSMKK531 NVVPSYDLLL541 EMLDAH
|
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|
|
MET343
3.747
LEU346
3.353
THR347
3.577
LEU349
4.091
ALA350
3.636
ASP351
2.693
GLU353
2.454
LEU354
3.783
TRP383
3.757
LEU384
4.152
LEU387
3.693
MET388
3.921
LEU391
3.734
ARG394
3.022
|
|||||
| PDB ID: 1ERR HUMAN ESTROGEN RECEPTOR LIGAND-BINDING DOMAIN IN COMPLEX WITH RALOXIFENE | ||||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [3] |
| PDB Sequence |
ALSLTADQMV
316 SALLDAEPPI326 LYSEYDPTRP336 FSEASMMGLL346 TNLADRELVH356 MINWAKRVPG 366 FVDLTLHDQV376 HLLEAWLEIL387 MIGLVWRSME397 HPGKLLFAPN407 LLLDRNQGKC 417 VEGMVEIFDM427 LLATSSRFRM437 MNLQGEEFVC447 LKSIILLNSG457 VYEEKDHIHR 477 VLDKITDTLI487 HLMAKAGLTL497 QQQHQRLAQL507 LLILSHIRHM517 SNKGMEHLYS 527 MPLYDLLLEM543 LDAH
|
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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 .RAL or .RAL2 or .RAL3 or :3RAL;style chemicals stick;color identity;select .A:343 or .A:346 or .A:347 or .A:349 or .A:350 or .A:351 or .A:353 or .A:354 or .A:383 or .A:384 or .A:387 or .A:388 or .A:391 or .A:394 or .A:404 or .A:420 or .A:421 or .A:424 or .A:425 or .A:428 or .A:521 or .A:524 or .A:525 or .A:536 or .A:539; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343
4.011
LEU346
3.460
THR347
3.623
LEU349
4.425
ALA350
3.587
ASP351
2.664
GLU353
2.410
LEU354
3.472
TRP383
3.567
LEU384
4.137
LEU387
3.638
MET388
3.883
LEU391
3.848
|
|||||
| PDB ID: 2JFA ESTROGEN RECEPTOR ALPHA LBD IN COMPLEX WITH AN AFFINITY-SELECTED COREPRESSOR PEPTIDE | ||||||
| Method | X-ray diffraction | Resolution | 2.55 Å | Mutation | No | [4] |
| PDB Sequence |
> Chain A
SLALSLTADQ 314 MVSALLDAEP324 PILYSEYPFS338 EASMMGLLTN348 LADRELVHMI358 NWAKRVPGFV 368 DLTLHDQVHL378 LECAWLEILM388 IGLVWRSMEH398 PGKLLFAPNL408 LLDRNQGKCV 418 EGMVEIFDML428 LATSSRFRMM438 NLQGEEFVCL448 KSIILLNSGV458 YTFLSSTLKS 468 LEEKDHIHRV478 LDKITDTLIH488 LMAKAGLTLQ498 QQHQRLAQLL508 LILSHIRHMS 518 NKGMEHLYSM528 K> Chain B LALSLTADQM 315 VSALLDAEPP325 ILYSEYDPTR335 PFSEASMMGL345 LTNLADRELV355 HMINWAKRVP 365 GFVDLTLHDQ375 VHLLECAWLE385 ILMIGLVWRS395 MEHPGKLLFA405 PNLLLDRNQG 415 KVEGMVEIFD426 MLLATSSRFR436 MMNLQGEEFV446 CLKSIILLNS456 GVYTFLSSTL 466 KSLEEKDHIH476 RVLDKITDTL486 IHLMAKAGLT496 LQQQHQRLAQ506 LLLILSHIRH 516 MSNKGMEHLY526 SM
|
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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 .RAL or .RAL2 or .RAL3 or :3RAL;style chemicals stick;color identity;select .A:343 or .A:346 or .A:347 or .A:349 or .A:350 or .A:351 or .A:353 or .A:354 or .A:383 or .A:384 or .A:387 or .A:388 or .A:391 or .A:394 or .A:404 or .A:420 or .A:421 or .A:424 or .A:425 or .A:428 or .A:521 or .A:524 or .A:525 or .B:343 or .B:346 or .B:347 or .B:349 or .B:350 or .B:351 or .B:353 or .B:354 or .B:383 or .B:384 or .B:387 or .B:388 or .B:391 or .B:394 or .B:404 or .B:420 or .B:421 or .B:424 or .B:428 or .B:521 or .B:524 or .B:525; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343[A]
3.740
LEU346[A]
3.293
THR347[A]
3.494
LEU349[A]
4.456
ALA350[A]
3.494
ASP351[A]
2.826
GLU353[A]
2.567
LEU354[A]
3.390
TRP383[A]
3.578
LEU384[A]
4.217
LEU387[A]
3.666
MET388[A]
3.866
LEU391[A]
3.903
ARG394[A]
3.021
PHE404[A]
3.753
GLY420[A]
4.696
MET421[A]
3.012
ILE424[A]
3.024
PHE425[A]
4.902
LEU428[A]
3.825
GLY521[A]
4.259
HIS524[A]
2.796
LEU525[A]
3.796
MET343[B]
3.690
LEU346[B]
3.069
THR347[B]
3.528
LEU349[B]
4.334
ALA350[B]
3.542
ASP351[B]
2.790
GLU353[B]
2.440
LEU354[B]
3.586
TRP383[B]
3.570
LEU384[B]
4.300
LEU387[B]
3.749
MET388[B]
4.011
LEU391[B]
3.903
ARG394[B]
2.936
PHE404[B]
3.704
GLY420[B]
5.000
MET421[B]
2.940
ILE424[B]
3.334
LEU428[B]
4.008
GLY521[B]
3.926
HIS524[B]
2.635
LEU525[B]
3.717
|
|||||
| PDB ID: 7NDO ER-PRS*(-) (L536S, L372R) in complex with raloxifene | ||||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [5] |
| PDB Sequence |
TADQIISALL
320 EAEPPILYSE330 YDPSRPFSEA340 YMMGLLTNLA350 DRELVHMINW360 AKKVPGFVDL 370 SRHDQVHLLE380 SAWLEILMIG390 LVWRSMDHPG400 KLLFAPDLLL410 DREQGKSVEG 420 MVEIFDMLLA430 TSERFREMKL440 QREEFVCLKA450 IILLNSGVYT460 FKSLENKEKI 475 HRMLDKITDA485 LIWYMAKSGL495 SLQQQHQRLA505 QLLLILSHIR515 HMSNKGMEHL 525 YSMKSKNVVP535 SYDLLLEMLD545 AH
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .RAL or .RAL2 or .RAL3 or :3RAL;style chemicals stick;color identity;select .A:343 or .A:346 or .A:347 or .A:349 or .A:350 or .A:351 or .A:353 or .A:354 or .A:383 or .A:384 or .A:387 or .A:388 or .A:391 or .A:394 or .A:402 or .A:404 or .A:420 or .A:421 or .A:424 or .A:425 or .A:428 or .A:521 or .A:524 or .A:525 or .A:528 or .A:530 or .A:531 or .A:532 or .A:533 or .A:534 or .A:535 or .A:536 or .A:539 or .A:540; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343
3.036
LEU346
2.610
THR347
2.260
LEU349
2.873
ALA350
2.577
ASP351
2.265
GLU353
2.011
LEU354
2.134
TRP383
2.366
LEU384
3.469
LEU387
2.356
MET388
3.350
LEU391
2.355
ARG394
2.280
LEU402
4.789
PHE404
3.115
GLY420
4.540
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells. Elife. 2022 May 16;11:e72512. | ||||
| REF 2 | Coupling of receptor conformation and ligand orientation determine graded activity. Nat Chem Biol. 2010 Nov;6(11):837-43. | ||||
| REF 3 | Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997 Oct 16;389(6652):753-8. | ||||
| REF 4 | Structural insights into corepressor recognition by antagonist-bound estrogen receptors. J Biol Chem. 2007 Apr 6;282(14):10449-55. | ||||
| REF 5 | A PROSS-designed extensively mutated estrogen receptor Alpha variant displays enhanced thermal stability while retaining native allosteric regulation and structure. Sci Rep. 2021 May 18;11(1):10509. | ||||
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