Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T21123 Target Info
Target Name Hypoxia-inducible factor 2 alpha (HIF-2A)
Synonyms bHLHe73; PASD2; PAS domain-containing protein 2; Member of PAS protein 2; MOP2; Hypoxia-inducible factor 2-alpha; HLF; HIF2A; HIF2-alpha; HIF-2-alpha; HIF-1-alpha-like factor; Endothelial PAS domain-containing protein 1; EPAS-1; Class E basic helix-loop-helix protein 73; Basic-helix-loop-helix-PAS protein MOP2
Target Type Successful Target
Gene Name EPAS1
UniProt ID
EPAS1_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: PT2385 Ligand Info
Structure Description Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex PDB:5TBM
Method X-ray diffraction Resolution 1.85 Å Mutation Yes [1]
PDB Sequence
LDSKTFLSEH
248
SMDMKFTYCD
258
DRITELIGYH
268
PEELLGRSAY
278
EFYHALDSEN
288

MTKSHQNLCT
298
KGQVVSGQYR
308
MLAKHGGYVW
318
LETQGTVIYN
328
PPQCIMCVNY
342

VLSEIE
Residue
Distance (Å)
PHE244
3.178
SER246
3.697
HIS248
3.346
SER249
4.433
MET252
3.512
PHE254
3.854
ILE261
4.782
ALA277
3.298
PHE280
3.654
TYR281
3.240
MET289
3.685
SER292
3.622
HIS293
2.650
Residue
Distance (Å)
LEU296
3.091
VAL302
3.505
VAL303
4.769
SER304
3.286
TYR307
3.397
ARG308
4.364
MET309
3.008
LEU319
4.214
THR321
3.372
GLY323
3.846
ILE337
2.809
CYS339
3.430
ASN341
3.288
Ligand Name: 2-(carboxymethylamino)-2-oxoacetic acid Ligand Info
Structure Description HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH N-OXALYLGLYCINE (NOG) AND HIF-2 ALPHA CODD (523-542) PDB:7Q5V
Method X-ray diffraction Resolution 1.17 Å Mutation No [2]
PDB Sequence
ELDLETLAPY
532
IPMDGEDFQL
542
Residue
Distance (Å)
PRO531
2.396
Residue
Distance (Å)
Ligand Name: Alpha-ketoglutaric acid Ligand Info
Structure Description HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-2 ALPHA CODD (523-542) PDB:7Q5X
Method X-ray diffraction Resolution 1.21 Å Mutation No [3]
PDB Sequence
LDLETLAPYI
533
PMDGEDFQL
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AKG or .AKG2 or .AKG3 or :3AKG;style chemicals stick;color identity;select .B:531; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PRO531
2.408
Residue
Distance (Å)
Ligand Name: N-(3-Chloro-5-Fluorophenyl)-4-Nitro-2,1,3-Benzoxadiazol-5-Amine Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist PDB:4GHI
Method X-ray diffraction Resolution 1.50 Å Mutation Yes [4]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYPQCIMCVN
341

YVLSEIE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .0X3 or .0X32 or .0X33 or :30X3;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:265 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
2.387
SER246
2.078
HIS248
2.423
MET252
3.415
PHE254
3.000
ILE261
4.310
ILE265
4.783
ALA277
2.169
PHE280
3.027
TYR281
1.821
MET289
3.324
SER292
2.783
Residue
Distance (Å)
HIS293
3.287
LEU296
2.928
VAL302
2.899
SER304
2.627
TYR307
2.408
MET309
2.690
LEU319
3.556
THR321
2.589
GLY323
4.751
ILE337
2.585
CYS339
2.968
ASN341
2.753
Ligand Name: N-(furan-2-ylmethyl)-2-nitro-4-(trifluoromethyl)aniline Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS020 PDB:3H82
Method X-ray diffraction Resolution 1.50 Å Mutation Yes [5]
PDB Sequence
EFKGLDSKTF
244
LSEHSMDMKF
254
TYCDDRITEL
264
IGYHPEELLG
274
RSAYEFYHAL
284

DSENMTKSHQ
294
NLCTKGQVVS
304
GQYRMLAKHG
314
GYVWLETQGT
324
VIYNPRNLQP
334

QCIMCVNYVL
344
SEIEK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .020 or .0202 or .0203 or :3020;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
4.994
SER246
3.814
HIS248
2.885
MET252
3.053
PHE254
3.626
ALA277
3.251
PHE280
3.831
TYR281
3.328
MET289
3.109
SER292
3.334
HIS293
3.754
LEU296
3.899
Residue
Distance (Å)
VAL302
3.148
VAL303
4.880
SER304
3.378
TYR307
3.204
MET309
3.607
LEU319
4.208
THR321
3.521
GLY323
4.484
ILE337
3.588
CYS339
3.513
ASN341
3.675
Ligand Name: N-(3-chloro-5-fluorophenyl)-2-nitro-4-[(trifluoromethyl)sulfonyl]aniline Ligand Info
Structure Description Crystal structure of PT1614 bound to HIF2a-B*:ARNT-B* complex PDB:6D0B
Method X-ray diffraction Resolution 1.60 Å Mutation Yes [6]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPPQCIMC
339

VNYVLSEIE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOV or .FOV2 or .FOV3 or :3FOV;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.131
SER246
3.482
HIS248
3.146
MET252
3.370
PHE254
3.672
ILE261
4.781
ALA277
3.699
PHE280
3.741
TYR281
3.322
MET289
3.179
SER292
3.399
HIS293
3.623
LEU296
3.398
Residue
Distance (Å)
VAL302
2.665
VAL303
3.564
SER304
3.310
TYR307
3.365
MET309
3.560
LEU319
3.966
THR321
3.026
GLN322
4.362
GLY323
3.378
ILE337
3.237
CYS339
3.479
ASN341
3.243
Ligand Name: N-[2-Nitro-4-(Trifluoromethyl)phenyl]morpholin-4-Amine Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains, with an internally-bound artificial ligand PDB:3F1O
Method X-ray diffraction Resolution 1.60 Å Mutation Yes [7]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPQCIMCV
340

NYVLSEIEK
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .2XY or .2XY2 or .2XY3 or :32XY;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.581
SER246
2.896
HIS248
3.269
MET252
3.501
PHE254
2.659
ALA277
2.753
PHE280
3.801
TYR281
3.048
MET289
2.987
SER292
2.779
HIS293
2.510
LEU296
3.167
Residue
Distance (Å)
VAL302
2.471
VAL303
4.783
SER304
2.617
TYR307
3.375
MET309
2.964
LEU319
3.621
THR321
3.004
GLN322
4.760
GLY323
3.431
ILE337
2.856
CYS339
2.629
ASN341
3.340
Ligand Name: {2-Bromo-3-(3-chloro-5-fluorophenoxy)-6-[(difluoromethyl)sulfonyl]phenyl}methanol Ligand Info
Structure Description Crystal structure of PT1940 bound to HIF2a-B*:ARNT-B* complex PDB:6CZW
Method X-ray diffraction Resolution 1.60 Å Mutation Yes [8]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPPQCIMC
339

VNYVLSEIE
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FO7 or .FO72 or .FO73 or :3FO7;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.266
SER246
3.634
HIS248
3.416
MET252
3.389
PHE254
3.842
ILE261
4.925
ALA277
3.622
PHE280
3.729
TYR281
3.353
MET289
2.993
SER292
3.510
HIS293
2.958
LEU296
3.385
Residue
Distance (Å)
VAL302
3.540
VAL303
4.682
SER304
3.205
TYR307
3.425
MET309
3.598
LEU319
3.823
THR321
3.416
GLN322
4.791
GLY323
3.513
ILE337
3.984
CYS339
3.586
ASN341
3.154
Ligand Name: 2-nitro-N-(thiophen-3-ylmethyl)-4-(trifluoromethyl)aniline Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS017 PDB:3H7W
Method X-ray diffraction Resolution 1.65 Å Mutation Yes [5]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYPQCIMCVN
341

YVLSEIEK
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .018 or .0182 or .0183 or :3018;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
4.647
SER246
3.793
HIS248
2.880
MET252
2.535
PHE254
4.096
ALA277
3.021
PHE280
4.530
TYR281
2.891
MET289
2.976
SER292
3.170
HIS293
3.506
Residue
Distance (Å)
LEU296
3.882
VAL302
3.239
VAL303
4.753
SER304
3.303
TYR307
3.494
MET309
3.602
LEU319
4.206
THR321
3.384
ILE337
3.809
CYS339
3.431
ASN341
3.417
Ligand Name: (5s,7r)-5,7-Bis(3-Bromophenyl)-4,5,6,7-Tetrahydrotetrazolo[1,5-A]pyrimidine Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a tetrazole-containing antagonist PDB:4XT2
Method X-ray diffraction Resolution 1.70 Å Mutation Yes [9]
PDB Sequence
GEFKGLDSKT
243
FLSEHSMDMK
253
FTYCDDRITE
263
LIGYHPEELL
273
GRSAYEFYHA
283

LDSENMTKSH
293
QNLCTKGQVV
303
SGQYRMLAKH
313
GGYVWLETQG
323
TVIYNPRNLQ
333

PQCIMCVNYV
343
LSEIEK
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .43L or .43L2 or .43L3 or :343L;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:249 or .A:252 or .A:253 or .A:254 or .A:261 or .A:265 or .A:277 or .A:280 or .A:281 or .A:289 or .A:290 or .A:292 or .A:293 or .A:295 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
2.488
SER246
2.383
HIS248
2.563
SER249
4.399
MET252
2.430
LYS253
4.579
PHE254
3.153
ILE261
4.426
ILE265
4.735
ALA277
2.358
PHE280
2.819
TYR281
2.606
MET289
2.610
THR290
4.828
SER292
2.360
Residue
Distance (Å)
HIS293
2.554
ASN295
4.923
LEU296
2.956
VAL302
3.049
VAL303
3.940
SER304
3.074
TYR307
2.758
MET309
2.696
LEU319
3.117
THR321
2.485
GLN322
4.615
GLY323
2.965
ILE337
3.267
CYS339
1.986
ASN341
2.686
Ligand Name: N-(3-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine Ligand Info
Structure Description Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist PDB:4GS9
Method X-ray diffraction Resolution 1.72 Å Mutation Yes [10]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYPQCIMCVN
341

YVLSEIE
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .0XB or .0XB2 or .0XB3 or :30XB;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:265 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
2.291
SER246
2.008
HIS248
2.108
MET252
2.228
PHE254
3.289
ILE261
4.310
ILE265
4.368
ALA277
2.176
PHE280
3.609
TYR281
1.810
MET289
3.763
SER292
3.013
Residue
Distance (Å)
HIS293
3.201
LEU296
3.239
VAL302
3.097
SER304
2.770
TYR307
2.277
MET309
2.527
LEU319
3.089
THR321
2.447
GLY323
4.999
ILE337
3.140
CYS339
2.844
ASN341
2.813
Ligand Name: HIF-2alpha-IN-1 Ligand Info
Structure Description Crystal structure of PT2440 bound to HIF2a-B*:ARNT-B* complex PDB:6D09
Method X-ray diffraction Resolution 1.85 Å Mutation Yes [11]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPPQCIMC
339

VNYVLSE
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FOJ or .FOJ2 or .FOJ3 or :3FOJ;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:308 or .A:309 or .A:319 or .A:321 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.244
SER246
3.535
HIS248
3.260
MET252
3.171
PHE254
3.782
ILE261
4.704
ALA277
3.312
PHE280
3.421
TYR281
3.338
MET289
3.422
SER292
3.271
HIS293
2.815
LEU296
3.262
Residue
Distance (Å)
VAL302
3.359
VAL303
4.636
SER304
3.181
TYR307
3.401
ARG308
4.534
MET309
3.155
LEU319
4.123
THR321
3.614
GLY323
3.542
ILE337
3.250
CYS339
3.475
ASN341
3.244
Ligand Name: 1-(3-Bromo-5-fluorophenoxy)-4-[(difluoromethyl)sulfonyl]-2-nitrobenzene Ligand Info
Structure Description Crystal structure of PT1673 bound to HIF2a-B*:ARNT-B* complex PDB:6X21
Method X-ray diffraction Resolution 1.54 Å Mutation Yes [12]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYPQCIMCVN
341

YVLSEIE
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .UKJ or .UKJ2 or .UKJ3 or :3UKJ;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.152
SER246
3.721
HIS248
3.153
MET252
3.347
PHE254
3.906
ILE261
4.914
ALA277
3.557
PHE280
3.608
TYR281
3.402
MET289
3.262
SER292
3.199
HIS293
3.388
LEU296
3.568
Residue
Distance (Å)
VAL302
3.302
VAL303
4.386
SER304
3.243
TYR307
3.341
MET309
3.656
LEU319
3.860
THR321
3.480
GLN322
4.767
GLY323
3.333
ILE337
3.226
CYS339
3.388
ASN341
3.284
Ligand Name: 3-({(1s)-7-[(Difluoromethyl)sulfonyl]-2,2-Difluoro-1-Hydroxy-2,3-Dihydro-1h-Inden-4-Yl}oxy)-5-Fluorobenzonitrile Ligand Info
Structure Description Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex PDB:5UFP
Method X-ray diffraction Resolution 1.90 Å Mutation Yes [13]
PDB Sequence
LDSKTFLSEH
248
SMDMKFTYCD
258
DRITELIGYH
268
PEELLGRSAY
278
EFYHALDSEN
288

MTKSHQNLCT
298
KGQVVSGQYR
308
MLAKHGGYVW
318
LETQGTVIYN
328
PPQCIMCVNY
342

VLSE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .86D or .86D2 or .86D3 or :386D;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:249 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:308 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.294
SER246
3.748
HIS248
3.387
SER249
4.465
MET252
3.459
PHE254
3.905
ILE261
4.738
ALA277
3.397
PHE280
3.504
TYR281
3.287
MET289
3.091
SER292
3.169
HIS293
2.582
LEU296
3.109
Residue
Distance (Å)
VAL302
3.915
VAL303
4.638
SER304
3.349
TYR307
3.441
ARG308
4.348
MET309
3.042
LEU319
4.019
THR321
3.437
GLN322
4.625
GLY323
3.813
ILE337
3.013
CYS339
3.458
ASN341
3.136
Ligand Name: (1R)-4-(3,5-difluorophenoxy)-7-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol Ligand Info
Structure Description Crystal structure of PT2243 bound to HIF2a-B*:ARNT-B* complex PDB:6X28
Method X-ray diffraction Resolution 1.92 Å Mutation No [14]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPPQCIMC
339

VNYVLS
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ULG or .ULG2 or .ULG3 or :3ULG;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.192
SER246
3.653
HIS248
3.480
MET252
3.338
PHE254
3.954
ILE261
4.835
ALA277
3.214
PHE280
3.890
TYR281
3.319
MET289
3.489
SER292
3.755
HIS293
2.555
Residue
Distance (Å)
LEU296
3.309
VAL302
3.342
SER304
3.210
TYR307
3.488
MET309
3.358
LEU319
3.900
THR321
3.512
GLY323
3.929
ILE337
3.842
CYS339
3.737
ASN341
3.146
Ligand Name: 3-fluoro-5-{[(7R)-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]oxy}benzonitrile Ligand Info
Structure Description Crystal structure of PT3245 bound to HIF2a-B*:ARNT-B* complex PDB:6X37
Method X-ray diffraction Resolution 1.94 Å Mutation Yes [15]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPQCIMCV
340

NYVLSEIE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ULS or .ULS2 or .ULS3 or :3ULS;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:252 or .A:254 or .A:261 or .A:277 or .A:280 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:308 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.363
SER246
3.721
HIS248
3.512
MET252
3.627
PHE254
3.992
ILE261
4.994
ALA277
3.342
PHE280
3.464
TYR281
3.330
MET289
3.499
SER292
3.686
HIS293
2.649
LEU296
3.136
Residue
Distance (Å)
VAL302
3.335
VAL303
4.941
SER304
3.313
TYR307
3.529
ARG308
4.623
MET309
3.071
LEU319
4.143
THR321
3.505
GLN322
4.970
GLY323
3.864
ILE337
4.137
CYS339
3.767
ASN341
3.235
Ligand Name: (6R,7S)-4-[(3,3-difluorocyclobutyl)oxy]-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol Ligand Info
Structure Description Crystal structure of PT3388 bound to HIF2a-B*:ARNT-B* complex PDB:6X3D
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [16]
PDB Sequence
KGLDSKTFLS
246
EHSMDMKFTY
256
CDDRITELIG
266
YHPEELLGRS
276
AYEFYHALDS
286

ENMTKSHQNL
296
CTKGQVVSGQ
306
YRMLAKHGGY
316
VWLETQGTVI
326
YPQCIMCVNY
342

VLSE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ULM or .ULM2 or .ULM3 or :3ULM;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:249 or .A:252 or .A:254 or .A:265 or .A:277 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:304 or .A:307 or .A:309 or .A:319 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.438
SER246
3.305
HIS248
3.561
SER249
4.352
MET252
3.368
PHE254
3.326
ILE265
4.998
ALA277
3.353
TYR281
3.023
MET289
3.440
SER292
3.874
HIS293
2.602
Residue
Distance (Å)
LEU296
3.443
VAL302
3.394
SER304
3.523
TYR307
3.435
MET309
3.533
LEU319
3.491
THR321
3.390
GLN322
4.967
GLY323
3.692
ILE337
3.466
CYS339
3.821
ASN341
3.101
Ligand Name: cis-3-({(1S)-7-[dihydroxy(trifluoromethyl)-lambda~4~-sulfanyl]-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl}oxy)cyclobutane-1-carbonitrile Ligand Info
Structure Description Crystal structure of PT2863 bound to HIF2a-B*:ARNT-B* complex PDB:6X2H
Method X-ray diffraction Resolution 2.00 Å Mutation No [17]
PDB Sequence
FKGLDSKTFL
245
SEHSMDMKFT
255
YCDDRITELI
265
GYHPEELLGR
275
SAYEFYHALD
285

SENMTKSHQN
295
LCTKGQVVSG
305
QYRMLAKHGG
315
YVWLETQGTV
325
IYNPPQCIMC
339

VNYVLSEIE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ULD or .ULD2 or .ULD3 or :3ULD;style chemicals stick;color identity;select .A:244 or .A:246 or .A:248 or .A:249 or .A:252 or .A:254 or .A:257 or .A:261 or .A:265 or .A:277 or .A:281 or .A:289 or .A:292 or .A:293 or .A:296 or .A:302 or .A:303 or .A:304 or .A:307 or .A:309 or .A:321 or .A:322 or .A:323 or .A:337 or .A:339 or .A:341; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE244
3.198
SER246
3.791
HIS248
3.695
SER249
4.376
MET252
3.421
PHE254
3.408
CYS257
4.555
ILE261
3.543
ILE265
4.918
ALA277
3.301
TYR281
3.185
MET289
3.249
SER292
3.322
Residue
Distance (Å)
HIS293
2.693
LEU296
3.249
VAL302
3.103
VAL303
4.796
SER304
3.469
TYR307
3.345
MET309
3.925
THR321
3.378
GLN322
4.185
GLY323
3.412
ILE337
3.043
CYS339
3.230
ASN341
3.303
References  Top
REF 1 A Small-Molecule Antagonist of HIF2Alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma. Cancer Res. 2016 Sep 15;76(18):5491-500.
REF 2 HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH N-OXALYLGLYCINE (NOG) AND HIF-2 ALPHA CODD (523-542)
REF 3 HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2_OXOGLUTARATE (2OG) AND HIF-2 ALPHA CODD (523-542)
REF 4 Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol. 2013 Apr;9(4):271-6.
REF 5 Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B. J Am Chem Soc. 2009 Dec 9;131(48):17647-54.
REF 6 Crystal structure of PT1614 bound to HIF2a-B*:ARNT-B* complex
REF 7 Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):450-5.
REF 8 Crystal structure of PT1940 bound to HIF2a-B*:ARNT-B* complex
REF 9 Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2. J Med Chem. 2015 Aug 13;58(15):5930-41.
REF 10 Development of inhibitors of the PAS-B domain of the HIF-2 transcription factor. J Med Chem. 2013 Feb 28;56(4):1739-47.
REF 11 Crystal structure of PT1940 bound to HIF2a-B*:ARNT-B* complex
REF 12 Crystal structure of PT1673 bound to HIF2a-B*:ARNT-B* complex
REF 13 On-target efficacy of a HIF-2Alpha antagonist in preclinical kidney cancer models. Nature. 2016 Nov 3;539(7627):107-111.
REF 14 Crystal structure of PT2243 bound to HIF2-PasB*:ARNT-PasB* complex
REF 15 Crystal structure of PT3245 bound to HIF2a-B*:ARNT-B* complex
REF 16 Crystal structure of PT3388 bound to HIF2a-B*:ARNT-B* complex
REF 17 Crystal structure of PT2863 bound to HIF2a-B*:ARNT-B* complex

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