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 | Afimoxifene | Ligand Info | |||
| Canonical SMILES | CCC(=C(C1=CC=C(C=C1)O)C2=CC=C(C=C2)OCCN(C)C)C3=CC=CC=C3 | ||||
| InChI | 1S/C26H29NO2/c1-4-25(20-8-6-5-7-9-20)26(21-10-14-23(28)15-11-21)22-12-16-24(17-13-22)29-19-18-27(2)3/h5-17,28H,4,18-19H2,1-3H3/b26-25- | ||||
| InChIKey | TXUZVZSFRXZGTL-QPLCGJKRSA-N | ||||
| PubChem Compound ID | 449459 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7UJ8 Estrogen Receptor Alpha Ligand Binding Domain Y537S in Complex with 4-Hydroxytamoxifen | ||||||
| Method | X-ray diffraction | Resolution | 2.38 Å | Mutation | Yes | [1] |
| PDB Sequence |
SLTADQMVSA
318 LLDAEPPILY328 SEPFSEASMM343 GLLTNLADRE353 LVHMINWAKR363 VPGFVDLTLH 373 DQVHLLESAW383 LEILMIGLVW393 RSMEHPGKLL403 FAPNLLLDRN413 QGKSVEGMVE 423 IFDMLLATSS433 RFRMMNLQGE443 EFVCLKSIIL453 LNSGDHIHRV478 LDKITDTLIH 488 LMAKAGLTLQ498 QQHQRLAQLL508 LILSHIRHMS518 NKGMEHLYSM528 KSPLSDLLLE 542 MLD
|
|||||
|
|
MET343
3.937
LEU346
3.620
THR347
3.608
LEU349
4.450
ALA350
3.526
ASP351
3.401
GLU353
2.508
TRP383
3.743
LEU384
4.023
LEU387
3.934
|
|||||
| PDB ID: 6V87 Estrogen Receptor Alpha Ligand Binding Domain Y537S in Complex with 4-Hydroxytamoxifen | ||||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | Yes | [2] |
| PDB Sequence |
SLTADQMVSA
318 LLDAEPPILY328 SEPFSEASMM343 GLLTNLADRE353 LVHMINWAKR363 VPGFVDLTLH 373 DQVHLLESAW383 LEILMIGLVW393 RSMEHPGKLL403 FAPNLLLDRN413 QGKSVEGMVE 423 IFDMLLATSS433 RFRMMNLQGE443 EFVCLKSIIL453 LNSGDHIHRV478 LDKITDTLIH 488 LMAKAGLTLQ498 QQHQRLAQLL508 LILSHIRHMS518 NKGMEHLYSM528 KSPLSDLLLE 542 MLD
|
|||||
|
|
MET343
3.847
LEU346
3.534
THR347
3.617
LEU349
4.448
ALA350
3.572
ASP351
3.507
GLU353
2.425
TRP383
3.776
LEU384
4.031
LEU387
3.876
|
|||||
| PDB ID: 3ERT HUMAN ESTROGEN RECEPTOR ALPHA LIGAND-BINDING DOMAIN IN COMPLEX WITH 4-HYDROXYTAMOXIFEN | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [3] |
| PDB Sequence |
LALSLTADQM
315 VSALLDAEPP325 ILYSEYDPTR335 PFSEASMMGL345 LTNLADRELV355 HMINWAKRVP 365 GFVDLTLHDQ375 VHLLECAWLE385 ILMIGLVWRS395 MEHPGKLLFA405 PNLLLDRNQG 415 KCVEGMVEIF425 DMLLATSSRF435 RMMNLQGEEF445 VCLKSIILLN455 SGVYTFLSST 465 LKSLEEKDHI475 HRVLDKITDT485 LIHLMAKAGL495 TLQQQHQRLA505 QLLLILSHIR 515 HMSNKGMEHL525 YSMKCKNVVP535 LYDLLLEMLD545 AHRLHAP
|
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|
|
MET343
3.770
LEU346
3.591
THR347
3.721
LEU349
4.065
ALA350
3.290
ASP351
3.201
GLU353
2.421
TRP383
3.706
LEU384
3.971
LEU387
3.675
MET388
4.386
|
|||||
| PDB ID: 4Q50 The Estrogen Receptor Alpha Ligand Binding Domain D538G Mutant in Complex with 4-hydroxytamoxifen | ||||||
| Method | X-ray diffraction | Resolution | 3.07 Å | Mutation | Yes | [4] |
| PDB Sequence |
ALSLTADQMV
316 SALLDAEPPI326 LYSMMGLLTN348 LADRELVHMI358 NWAKRVPGFV368 DLTLHDQVHL 378 LECAWLEILM388 IGLVWRSMEH398 PKLLFAPNLL409 LDRNQGKGMV422 EIFDMLLATS 432 SRFRMMNLQG442 EEFVCLKSII452 LLNSGVYSLE470 EKDHIHRVLD480 KITDTLIHLM 490 AKAGLTLQQQ500 HQRLAQLLLI510 LSHIRHMSNK520 GMEHLYSVVP535 LYGLLLEMLD 545
|
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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 .OHT or .OHT2 or .OHT3 or :3OHT;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:421 or .A:424 or .A:425 or .A:428 or .A:521 or .A:524 or .A:525 or .A:533 or .A:535; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343
4.137
LEU346
3.422
THR347
4.157
LEU349
4.279
ALA350
3.388
ASP351
2.578
GLU353
2.532
LEU354
4.460
TRP383
3.747
LEU384
3.816
LEU387
3.600
MET388
4.413
|
|||||
| PDB ID: 2BJ4 ESTROGEN RECEPTOR ALPHA LBD IN COMPLEX WITH A PHAGE-DISPLAY DERIVED PEPTIDE ANTAGONIST | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [5] |
| PDB Sequence |
> Chain A
SLALSLTADQ 314 MVSALLDAEP324 PILYSEPFSE339 ASMMGLLTNL349 ADRELVHMIN359 WAKRVPGFVD 369 LTLHDQVHLL379 ECAWLEILMI389 GLVWRSMEHP399 GKLLFAPNLL409 LDRNQGKCVE 419 GMVEIFDMLL429 ATSSRFRMMN439 LQGEEFVCLK449 SIILLNSGVY459 TFLSTLKSLE 470 EKDHIHRVLD480 KITDTLIHLM490 AKAGLTLQQQ500 HQRLAQLLLI510 LSHIRHMSNK 520 GMEHLYSM> Chain B NSLALSLTAD 313 QMVSALLDAE323 PPILYSEYDP333 TRPFSEASMM343 GLLTNLADRE353 LVHMINWAKR 363 VPGFVDLTLH373 DQVHLLECAW383 LEILMIGLVW393 RSMEHPGKLL403 FAPNLLLDRN 413 QGKVEGMVEI424 FDMLLATSSR434 FRMMNLQGEE444 FVCLKSIILL454 NSGVYTTLKS 468 LEEKDHIHRV478 LDKITDTLIH488 LMAKAGLTLQ498 QQHQRLAQLL508 LILSHIRHMS 518 NKGMEHLYSM528 K
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .OHT or .OHT2 or .OHT3 or :3OHT;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: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:421 or .B:424 or .B:425 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]
3.951
LEU346[A]
3.589
THR347[A]
3.633
LEU349[A]
4.192
ALA350[A]
3.322
ASP351[A]
2.681
GLU353[A]
2.702
LEU354[A]
3.524
TRP383[A]
3.731
LEU384[A]
3.871
LEU387[A]
3.908
MET388[A]
4.101
LEU391[A]
4.190
ARG394[A]
3.081
PHE404[A]
3.617
MET421[A]
3.493
ILE424[A]
3.808
PHE425[A]
4.318
LEU428[A]
3.557
GLY521[A]
3.689
HIS524[A]
4.044
LEU525[A]
3.784
MET343[B]
3.358
LEU346[B]
3.552
THR347[B]
3.634
LEU349[B]
4.440
ALA350[B]
3.508
ASP351[B]
2.579
GLU353[B]
2.636
LEU354[B]
3.598
TRP383[B]
3.675
LEU384[B]
3.827
LEU387[B]
3.837
MET388[B]
4.386
LEU391[B]
4.012
ARG394[B]
3.212
PHE404[B]
3.652
MET421[B]
3.649
ILE424[B]
3.646
PHE425[B]
4.228
LEU428[B]
3.734
GLY521[B]
3.649
HIS524[B]
3.574
LEU525[B]
3.729
|
|||||
| PDB ID: 2JF9 ESTROGEN RECEPTOR ALPHA LBD IN COMPLEX WITH A TAMOXIFEN-SPECIFIC PEPTIDE ANTAGONIST | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [6] |
| PDB Sequence |
SLALSLTADQ
314 MVSALLDAEP324 PILYSEYDPT334 RPFSEASMMG344 LLTNLADREL354 VHMINWAKRV 364 PGFVDLTLHD374 QVHLLECAWL384 EILMIGLVWR394 SMEHPGKLLF404 APNLLLDRNQ 414 GKCVEGMVEI424 FDMLLATSSR434 FRMMNLQGEE444 FVCLKSIILL454 NSGVYTEEKD 473 HIHRVLDKIT483 DTLIHLMAKA493 GLTLQQQHQR503 LAQLLLILSH513 IRHMSNKGME 523 HLYSM
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .OHT or .OHT2 or .OHT3 or :3OHT;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:421 or .A:424 or .A:425 or .A:428 or .A:521 or .A:524 or .A:525 or .A:528; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343
3.530
LEU346
3.630
THR347
3.639
LEU349
4.246
ALA350
3.355
ASP351
2.736
GLU353
2.622
LEU354
3.809
TRP383
3.659
LEU384
3.682
LEU387
3.762
MET388
4.250
|
|||||
| PDB ID: 5W9C Estrogen Receptor Alpha Ligand Binding Domain C381S, C417S, C530S in Complex with 4-hydroxytamoxifen | ||||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | Yes | [7] |
| PDB Sequence |
SLTADQMVSA
318 LLDAEPPILY328 SDPTRPFSEA340 SMMGLLTNLA350 DRELVHMINW360 AKRVPGFVDL 370 TLHDQVHLLE380 SAWLEILMIG390 LVWRSMEHPG400 KLLFAPNLLL410 DRNQGKSEMV 422 EIFDMLLATS432 SRFRMMNLQG442 EEFVCLKSII452 LLNSGVYTFS464 TLKSLEEKDH 474 IHRVLDKITD484 TLIHLMAKAG494 LTLQQQHQRL504 AQLLLILSHI514 RHMSNKGMEH 524 LYSMKSKNVV534 PSYDLLLEML544 DAH
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .OHT or .OHT2 or .OHT3 or :3OHT;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:421 or .A:424 or .A:428 or .A:521 or .A:524 or .A:525 or .A:532 or .A:533 or .A:534 or .A:535; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET343
3.868
LEU346
3.483
THR347
3.632
LEU349
3.970
ALA350
3.470
ASP351
2.462
GLU353
2.561
LEU354
4.749
TRP383
3.849
LEU384
3.880
LEU387
3.728
MET388
4.104
LEU391
4.234
|
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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 | Estrogen Receptor Alpha | ||||
| REF 3 | The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998 Dec 23;95(7):927-37. | ||||
| REF 4 | Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife. 2016 Feb 2;5:e12792. | ||||
| REF 5 | Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3593-8. | ||||
| REF 6 | Structural insights into corepressor recognition by antagonist-bound estrogen receptors. J Biol Chem. 2007 Apr 6;282(14):10449-55. | ||||
| REF 7 | Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer. Mol Pharmacol. 2018 Aug;94(2):812-822. | ||||
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