Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
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
ESR1_HUMAN
Ligand General Information  Top
Ligand Name (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol Ligand Info
Canonical SMILES CC1=C(C(OC2=C1C=C(C=C2)O)C3=CC=C(C=C3)I)C4=CC(=CC=C4)O
InChI 1S/C22H17IO3/c1-13-19-12-18(25)9-10-20(19)26-22(14-5-7-16(23)8-6-14)21(13)15-3-2-4-17(24)11-15/h2-12,22,24-25H,1H3/t22-/m0/s1
InChIKey RWKXMXMLZHFKIZ-QFIPXVFZSA-N
PubChem Compound ID 137332066
Drug Binding Sites of Target  Top
PDB ID: 6DFN      Crystal structure of estrogen receptor alpha in complex with receptor degrader 16aa
Method X-ray diffraction Resolution 2.10 Å Mutation No [1]
PDB Sequence
LALSLTADQM
315
VSALLDAEPP
325
ILYSEYDPTR
335
PFSEASMMGL
345
LTNLADRELV
355

HMINWAKRVP
365
GFVDLTSHDQ
375
VHLLECAWLE
385
ILMIGLVWRS
395
MEHPGKLLFA
405

PNLLLDRNQG
415
KCVEGMVEIF
425
DMLLATSSRF
435
RMMNLQGEEF
445
VCLKSIILLN
455

SGVYTFTLKS
468
LEEKDHIHRV
478
LDKITDTLIH
488
LMAKAGLTLQ
498
QQHQRLAQLL
508

LILSHIRHMS
518
NKGMEHLYSM
528
VVPSYDLLLE
542
MLDA
Residue
Distance (Å)
MET343
4.059
LEU346
3.403
THR347
3.391
LEU349
3.994
ALA350
3.487
ASP351
4.340
GLU353
2.517
TRP383
3.979
LEU384
4.356
LEU387
3.504
MET388
3.848
LEU391
3.870
Residue
Distance (Å)
ARG394
3.159
PHE404
3.820
MET421
3.192
ILE424
3.133
PHE425
4.068
LEU428
4.240
GLY521
4.081
HIS524
3.826
LEU525
3.944
VAL533
3.089
VAL534
4.517
PRO535
4.839
PDB ID: 6PET      Crystal structure of 8-hydroxychromene compound 30 bound to estrogen receptor alpha
Method X-ray diffraction Resolution 2.20 Å Mutation Yes [2]
PDB Sequence
LALSLTADQM
315
VSALLDAEPP
325
ILYSEYDPTR
335
PFSEASMMGL
345
LTNLADRELV
355

HMINWAKRVP
365
GFVDLTSHDQ
375
VHLLECAWLE
385
ILMIGLVWRS
395
MEHPGKLLFA
405

PNLLLDRNQG
415
KCVEGMVEIF
425
DMLLATSSRF
435
RMMNLQGEEF
445
VCLKSIILLN
455

SGVYTFTLKS
468
LEEKDHIHRV
478
LDKITDTLIH
488
LMAKAGLTLQ
498
QQHQRLAQLL
508

LILSHIRHMS
518
NKGMEHLYSM
528
KCKNVVPSYD
538
LLLEMLDA
Residue
Distance (Å)
MET343
3.233
LEU346
2.424
THR347
3.012
LEU349
3.437
ALA350
3.029
ASP351
4.507
GLU353
2.859
TRP383
3.312
LEU384
3.662
LEU387
2.914
MET388
3.063
LEU391
3.283
ARG394
2.581
Residue
Distance (Å)
PHE404
3.013
MET421
3.091
ILE424
2.741
PHE425
4.864
LEU428
3.422
GLY521
3.639
HIS524
2.107
LEU525
2.705
MET528
4.255
VAL533
4.309
VAL534
4.301
PRO535
4.854
PDB ID: 7MSA      GDC-9545 in complex with estrogen receptor alpha
Method X-ray diffraction Resolution 2.24 Å Mutation Yes [3]
PDB Sequence
LALSLTADQM
315
VSALLDAEPP
325
ILYSEYDPTR
335
PFSEASMMGL
345
LTNLADRELV
355

HMINWAKRVP
365
GFVDLTSHDQ
375
VHLLECAWLE
385
ILMIGLVWRS
395
MEHPGKLLFA
405

PNLLLDRNQG
415
KCVEGMVEIF
425
DMLLATSSRF
435
RMMNLQGEEF
445
VCLKSIILLN
455

SGVYTFTLKS
468
LEEKDHIHRV
478
LDKITDTLIH
488
LMAKAGLTLQ
498
QQHQRLAQLL
508

LILSHIRHMS
518
NKGMEHLYSM
528
KVVPSYDLLL
541
EMLD
Residue
Distance (Å)
MET343
4.492
LEU346
3.407
THR347
3.221
LEU349
4.146
ALA350
3.585
ASP351
4.241
GLU353
2.569
TRP383
4.066
LEU384
4.359
LEU387
3.494
MET388
3.786
LEU391
3.907
Residue
Distance (Å)
ARG394
3.173
PHE404
3.726
MET421
3.797
ILE424
3.504
LEU428
4.174
GLY521
2.655
MET522
4.419
HIS524
3.606
LEU525
3.279
VAL533
4.052
VAL534
4.775
PRO535
4.943
PDB ID: 6WOK      Crystal structure of estrogen receptor alpha in complex with receptor degrader 6
Method X-ray diffraction Resolution 2.31 Å Mutation Yes [4]
PDB Sequence
LALSLTADQM
315
VSALLDAEPP
325
ILYSEYDPTR
335
PFSEASMMGL
345
LTNLADRELV
355

HMINWAKRVP
365
GFVDLTSHDQ
375
VHLLECAWLE
385
ILMIGLVWRS
395
MEHPGKLLFA
405

PNLLLDRNQG
415
KCVEGMVEIF
425
DMLLATSSRF
435
RMMNLQGEEF
445
VCLKSIILLN
455

SGVYTFTLKS
468
LEEKDHIHRV
478
LDKITDTLIH
488
LMAKAGLTLQ
498
QQHQRLAQLL
508

LILSHIRHMS
518
NKGMEHLYSM
528
PSYDLLLEML
544
D
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .G9J or .G9J2 or .G9J3 or :3G9J;style chemicals stick;color identity;select .D:343 or .D:346 or .D:347 or .D:349 or .D:350 or .D:351 or .D:353 or .D:383 or .D:384 or .D:387 or .D:388 or .D:391 or .D:394 or .D:404 or .D:421 or .D:424 or .D:425 or .D:428 or .D:521 or .D:524 or .D:525; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET343
4.136
LEU346
3.445
THR347
3.704
LEU349
3.950
ALA350
3.602
ASP351
4.427
GLU353
2.998
TRP383
4.178
LEU384
4.273
LEU387
3.452
MET388
3.567
Residue
Distance (Å)
LEU391
4.155
ARG394
3.485
PHE404
3.663
MET421
3.076
ILE424
3.315
PHE425
4.586
LEU428
3.889
GLY521
3.687
HIS524
3.406
LEU525
3.680
References  Top
REF 1 Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha. Bioorg Med Chem Lett. 2019 Apr 1;29(7):905-911.
REF 2 Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927. Bioorg Med Chem Lett. 2019 Aug 15;29(16):2090-2093.
REF 3 GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer. J Med Chem. 2021 Aug 26;64(16):11841-11856.
REF 4 Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer. ACS Med Chem Lett. 2020 May 26;11(6):1342-1347.

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