Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T84780 Target Info
Target Name Cellular inhibitor of apoptosis 1 (BIRC2)
Synonyms hIAP2; hIAP-2; TNFR2TRAFsignaling complex protein 2; TNFR2-TRAF-signaling complex protein 2; RNF48; RING-type E3 ubiquitin transferase BIRC2; RING finger protein 48; MIHB; Inhibitor of apoptosis protein 2; IAP2; IAP homolog B; CIAP1; C-IAP1; Baculoviral IAP repeatcontaining protein 2; Baculoviral IAP repeat-containing protein 2; API1
Target Type Clinical trial Target
Gene Name BIRC2
Biochemical Class Acyltransferase
UniProt ID
BIRC2_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: PMID25980951-Compound-16 Ligand Info
Structure Description Crystal structure of cIAP1 BIR3 bound to T3256336 PDB:4HY5
Method X-ray diffraction Resolution 1.75 Å Mutation No [1]
PDB Sequence
GSSISNLSMQ
261
THAARMRTFM
271
YWPSSVPVQP
281
EQLASAGFYY
291
VGRNDDVKCF
301

CCDGGLRCWE
311
SGDDPWVEHA
321
KWFPRCEFLI
331
RMKGQEFVDE
341
IQGRY
Residue
Distance (Å)
VAL292
4.983
ASP297
3.660
VAL298
3.727
LYS299
3.983
GLY306
2.830
LEU307
3.422
ARG308
2.880
Residue
Distance (Å)
CYS309
3.242
TRP310
3.818
GLU311
3.471
ASP314
2.767
GLU319
3.596
TRP323
3.404
PHE324
4.183
Ligand Name: (3S,6S,7R,9aS)-N-benzyl-6-[[(2S)-2-(methylamino)propanoyl]amino]-5-oxo-7-[(propanoylamino)methyl]-3,6,7,8,9,9a-hexahydropyrrolo[1,2-a]azepine-3-carboxamide Ligand Info
Structure Description Crystal structure of cIAP1-BIR3 in complex with a covalently bound SM PDB:6EXW
Method X-ray diffraction Resolution 2.20 Å Mutation No [2]
PDB Sequence
SISNLSMQTH
263
AARMRTFMYW
273
PSSVPVQPEQ
283
LASAGFYYVG
293
RNDDVKCFCC
303

DGGLRCWESG
313
DDPWVEHAKW
323
FPRCEFLIRM
333
KGQEFVDEIQ
343
GRYPHLLE
Residue
Distance (Å)
ASP296
4.669
ARG308
3.140
Residue
Distance (Å)
CYS309
1.837
Ligand Name: (3s,6s,7r,9as)-6-{[(2s)-2-Aminobutanoyl]amino}-7-(2-Aminoethyl)-N-(Diphenylmethyl)-5-Oxooctahydro-1h-Pyrrolo[1,2-A]azepine-3-Carboxamide Ligand Info
Structure Description cIAP1-BIR3 domain in complex with the Smac-mimetic compound Smac037 PDB:3MUP
Method X-ray diffraction Resolution 2.60 Å Mutation No [3]
PDB Sequence
SISNLSMQTH
263
AARMRTFMYW
273
PSSVPVQPEQ
283
LASAGFYYVG
293
RNDDVKCFCC
303

DGGLRCWESG
313
DDPWVEHAKW
323
FPRCEFLIRM
333
KGQEFVDEIQ
343
GRYPHLLEQL
353

L
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SMK or .SMK2 or .SMK3 or :3SMK;style chemicals stick;color identity;select .A:292 or .A:294 or .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:322 or .A:323 or .A:324 or .A:353; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL292
4.558
ARG294
4.190
ASP297
3.939
VAL298
3.681
LYS299
3.537
GLY306
2.905
LEU307
3.347
ARG308
3.194
CYS309
3.207
Residue
Distance (Å)
TRP310
3.739
GLU311
3.601
ASP314
3.214
GLU319
3.080
LYS322
4.180
TRP323
3.520
PHE324
4.523
LEU353
4.316
Ligand Name: (3s,6s,7r,9as)-7-[2-(Benzylamino)ethyl]-N-(Diphenylmethyl)-6-{[(2s)-2-(Methylamino)butanoyl]amino}-5-Oxooctahydro-1h-Pyrrolo[1,2-A]azepine-3-Carboxamide Ligand Info
Structure Description cIAP1-BIR3 domain in complex with the Smac-mimetic compound Smac066 PDB:3OZ1
Method X-ray diffraction Resolution 3.00 Å Mutation No [3]
PDB Sequence
FSISNLSMQT
262
HAARMRTFMY
272
WPSSVPVQPE
282
QLASAGFYYV
292
GRNDDVKCFC
302

CDGGLRCWES
312
GDDPWVEHAK
322
WFPRCEFLIR
332
MKGQEFVDEI
342
QGRYPHLLEQ
352

LLS
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .BMB or .BMB2 or .BMB3 or :3BMB;style chemicals stick;color identity;select .A:292 or .A:294 or .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324 or .A:353; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL292
4.766
ARG294
4.206
ASP297
3.712
VAL298
3.877
LYS299
4.399
GLY306
3.013
LEU307
3.422
ARG308
3.117
Residue
Distance (Å)
CYS309
3.345
TRP310
3.781
GLU311
3.498
ASP314
3.085
GLU319
3.473
TRP323
3.506
PHE324
4.597
LEU353
3.645
Ligand Name: 1-[6-[(4-Fluorophenyl)methyl]-3,3-Dimethyl-2~{h}-Pyrrolo[3,2-B]pyridin-1-Yl]-2-[(2~{r},5~{r})-5-Methyl-2-[[(3~{r})-3-Methylmorpholin-4-Yl]methyl]piperazin-4-Ium-1-Yl]ethanone Ligand Info
Structure Description Small Molecule inhibitors of IAP PDB:5M6N
Method X-ray diffraction Resolution 1.80 Å Mutation No [4]
PDB Sequence
GSHMQTHAAR
266
MRTFMYWPSS
276
VPVQPEQLAS
286
AGFYYVGRND
296
DVKCFCCDGG
306

LRCWESGDDP
316
WVEHAKWFPR
326
CEFLIRMKGQ
336
EFVDEIQGRY
346
PHLLEQLLST
356
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .7H9 or .7H92 or .7H93 or :37H9;style chemicals stick;color identity;select .A:292 or .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL292
3.874
ASP297
3.585
VAL298
2.728
LYS299
3.382
GLY306
3.212
LEU307
2.620
ARG308
1.896
Residue
Distance (Å)
CYS309
2.216
TRP310
2.976
GLU311
3.683
ASP314
2.491
GLU319
2.710
TRP323
2.639
PHE324
3.004
Ligand Name: (3s,8ar)-2-{(2s)-2-Cyclohexyl-2-[(N-Methyl-L-Alanyl)amino]acetyl}-N-[(1r)-1,2,3,4-Tetrahydronaphthalen-1-Yl]octahydropyrrolo[1,2-A]pyrazine-3-Carboxamide Ligand Info
Structure Description Crystal structure of cIAP1 BIR3 bound to T3170284 PDB:4HY4
Method X-ray diffraction Resolution 1.25 Å Mutation No [1]
PDB Sequence
ISNLSMQTHA
264
ARMRTFMYWP
274
SSVPVQPEQL
284
ASAGFYYVGR
294
NDDVKCFCCD
304

GGLRCWESGD
314
DPWVEHAKWF
324
PRCEFLIRMK
334
GQEFVDEIQG
344
RY
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .1BG or .1BG2 or .1BG3 or :31BG;style chemicals stick;color identity;select .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASP297
3.703
VAL298
3.749
LYS299
4.045
GLY306
2.951
LEU307
3.318
ARG308
2.896
CYS309
3.574
Residue
Distance (Å)
TRP310
3.725
GLU311
3.500
ASP314
2.705
GLU319
2.943
TRP323
2.994
PHE324
3.813
Ligand Name: (4s,6ar,7as)-5-{(2s)-2-Cyclohexyl-2-[(N-Methyl-L-Alanyl)amino]acetyl}-N-[(4r)-3,4-Dihydro-2h-Chromen-4-Yl]octahydro-1h-Cyclopropa[4,5]pyrrolo[1,2-A]pyrazine-4-Carboxamide Ligand Info
Structure Description Crystal structure of clAP1 BIR3 bound to T3261256 PDB:4LGE
Method X-ray diffraction Resolution 1.55 Å Mutation No [5]
PDB Sequence
ISNLSMQTHA
264
ARMRTFMYWP
274
SSVPVQPEQL
284
ASAGFYYVGR
294
NDDVKCFCCD
304

GGLRCWESGD
314
DPWVEHAKWF
324
PRCEFLIRMK
334
GQEFVDEIQG
344
RY
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .1Y0 or .1Y02 or .1Y03 or :31Y0;style chemicals stick;color identity;select .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASP297
3.706
VAL298
3.770
LYS299
4.285
GLY306
2.937
LEU307
3.340
ARG308
2.921
CYS309
3.532
Residue
Distance (Å)
TRP310
3.707
GLU311
3.496
ASP314
2.750
GLU319
3.031
TRP323
2.929
PHE324
3.850
Ligand Name: (3s,10as)-2-[(2s)-2-Cyclohexyl-2-{[(2s)-2-(Methylamino)butanoyl]amino}acetyl]-N-[(4r)-3,4-Dihydro-2h-Chromen-4-Yl]-1,2,3,4,10,10a-Hexahydropyrazino[1,2-A]indole-3-Carboxamide Ligand Info
Structure Description Crystal structure of cIAP1 BIR3 bound to T3450325 PDB:4MU7
Method X-ray diffraction Resolution 1.79 Å Mutation No [6]
PDB Sequence
NLSMQTHAAR
266
MRTFMYWPSS
276
VPVQPEQLAS
286
AGFYYVGRND
296
DVKCFCCDGG
306

LRCWESGDDP
316
WVEHAKWFPR
326
CEFLIRMKGQ
336
EFVDEIQGRY
346
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .2DY or .2DY2 or .2DY3 or :32DY;style chemicals stick;color identity;select .A:294 or .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ARG294
3.571
ASP297
3.756
VAL298
3.618
LYS299
3.714
GLY306
2.800
LEU307
3.405
ARG308
2.942
Residue
Distance (Å)
CYS309
3.191
TRP310
3.819
GLU311
4.539
ASP314
2.705
GLU319
3.597
TRP323
3.703
PHE324
3.923
Ligand Name: (3s,8ar)-N-((R)-Chroman-4-Yl)-2-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propanamido)acetyl)octahydropyrrolo[1,2-A]pyrazine-3-Carboxamide Ligand Info
Structure Description Crystal structure of clAP1 BIR3 bound to T3226692 PDB:4LGU
Method X-ray diffraction Resolution 2.00 Å Mutation No [5]
PDB Sequence
NLSMQTHAAR
266
MRTFMYWPSS
276
VPVQPEQLAS
286
AGFYYVGRND
296
DVKCFCCDGG
306

LRCWESGDDP
316
WVEHAKWFPR
326
CEFLIRMKGQ
336
EFVDEIQGRY
346
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .1YH or .1YH2 or .1YH3 or :31YH;style chemicals stick;color identity;select .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:323 or .A:324; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASP297
3.656
VAL298
3.695
LYS299
4.191
GLY306
2.963
LEU307
3.305
ARG308
2.876
CYS309
3.392
Residue
Distance (Å)
TRP310
3.822
GLU311
3.714
ASP314
2.682
GLU319
3.316
TRP323
3.352
PHE324
3.901
Ligand Name: (3s,8ar)-2-[(2s)-2-Cyclohexyl-2-{[(2s)-2-(Methylamino)butanoyl]amino}acetyl]-N-[(4r)-3,4-Dihydro-2h-Chromen-4-Yl]octahydropyrrolo[1,2-A]pyrazine-3-Carboxamide Ligand Info
Structure Description Crystal structure of cIAP1 BIR3 bound to T3258042 PDB:4MTI
Method X-ray diffraction Resolution 2.15 Å Mutation No [6]
PDB Sequence
SSISNLSMQT
262
HAARMRTFMY
272
WPSSVPVQPE
282
QLASAGFYYV
292
GRNDDVKCFC
302

CDGGLRCWES
312
GDDPWVEHAK
322
WFPRCEFLIR
332
MKGQEFVDEI
342
QGRY
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Residue
Distance (Å)
ASP297
3.679
VAL298
3.645
LYS299
4.279
GLY306
2.723
LEU307
3.439
ARG308
2.937
CYS309
3.220
Residue
Distance (Å)
TRP310
3.667
GLU311
3.597
ASP314
2.758
GLU319
3.736
TRP323
3.378
PHE324
4.206
Ligand Name: (2s)-N-{(2r)-1-[(2r,4s)-2-{[6,6'-Difluoro-3'-({(2r,4s)-4-Hydroxy-1-[(2s)-2-{[(2s)-2-(Methylamino)propanoyl]amino}butanoyl]pyrrolidin-2-Yl}methyl)-1h,1'h-2,2'-Biindol-3-Yl]methyl}-4-Hydroxypyrrolidin-1-Yl]-1-Oxobutan-2-Yl}-2-(Methylamino)propanamide Ligand Info
Structure Description Structure of cIAP1-BIR3 and inhibitor PDB:4KMN
Method X-ray diffraction Resolution 1.52 Å Mutation No [7]
PDB Sequence
AAASISNLSM
260
QTHAARMRTF
270
MYWPSSVPVQ
280
PEQLASAGFY
290
YVGRNDDVKC
300

FCCDGGLRCW
310
ESGDDPWVEH
320
AKWFPRCEFL
330
IRMKGQEFVD
340
EIQGRYPHLL
350

EAA
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .436 or .4362 or .4363 or :3436;style chemicals stick;color identity;select .A:292 or .A:294 or .A:297 or .A:298 or .A:299 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:314 or .A:319 or .A:322 or .A:323 or .A:324; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL292
3.272
ARG294
2.544
ASP297
2.910
VAL298
4.107
LYS299
2.938
GLY306
3.108
LEU307
2.672
ARG308
1.966
Residue
Distance (Å)
CYS309
3.331
TRP310
3.547
GLU311
3.310
ASP314
2.589
GLU319
3.005
LYS322
4.716
TRP323
2.351
PHE324
3.664
Ligand Name: 2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl (3R)-3-[5-amino-4-carbamoyl-3-[4-(2,4-difluorophenoxy)phenyl]pyrazol-1-yl]piperidine-1-carboxylate Ligand Info
Structure Description Structure of cIAP with compound 15 PDB:6W74
Method X-ray diffraction Resolution 2.11 Å Mutation No [8]
PDB Sequence
MQTHAARMRT
275
FMYWPSSVPV
285
QPEQLASAGF
295
YYVGRNDDVK
305
CFCCDGGLRC
315

WESGDDPWVE
325
HAKWFPRCEF
335
LIRMKGQEFV
345
DEIQGRY
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .TKY or .TKY2 or .TKY3 or :3TKY;style chemicals stick;color identity;select .A:303 or .A:304 or .A:305 or .A:312 or .A:313 or .A:314 or .A:315 or .A:316 or .A:317 or .A:320 or .A:325 or .A:329 or .A:330; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASP303
3.622
VAL304
4.157
LYS305
3.741
GLY312
2.831
LEU313
3.456
ARG314
3.012
CYS315
3.734
Residue
Distance (Å)
TRP316
3.858
GLU317
4.493
ASP320
2.765
GLU325
3.163
TRP329
2.857
PHE330
3.739
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Ligand Name: BCPyr Ligand Info
Structure Description Ternary complex structure - BTK cIAP compound 17 PDB:6W7O
Method X-ray diffraction Resolution 2.17 Å Mutation No [9]
PDB Sequence
GSSISNLSMQ
267
THAARMRTFM
277
YWPSSVPVQP
287
EQLASAGFYY
297
VGRNDDVKCF
307

CCDGGLRCWE
317
SGDDPWVEHA
327
KWFPRCEFLI
337
RMKGQEFVDE
347
IQG
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .TL7 or .TL72 or .TL73 or :3TL7;style chemicals stick;color identity;select .C:303 or .C:304 or .C:305 or .C:312 or .C:313 or .C:314 or .C:315 or .C:316 or .C:317 or .C:320 or .C:325 or .C:329 or .C:330; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASP303
3.549
VAL304
4.025
LYS305
4.255
GLY312
2.799
LEU313
3.504
ARG314
2.851
CYS315
3.442
Residue
Distance (Å)
TRP316
3.763
GLU317
3.907
ASP320
2.985
GLU325
3.088
TRP329
3.033
PHE330
3.678
References  Top
REF 1 Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic. J Med Chem. 2013 Feb 14;56(3):1228-46.
REF 2 Structure-based design and molecular profiling of Smac-mimetics selective for cellular IAPs. FEBS J. 2018 Sep;285(17):3286-3298.
REF 3 Recognition of Smac-mimetic compounds by the BIR domain of cIAP1. Protein Sci. 2010 Dec;19(12):2418-29.
REF 4 Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP). J Med Chem. 2017 Jun 8;60(11):4611-4625.
REF 5 Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists. Bioorg Med Chem. 2013 Sep 15;21(18):5725-37.
REF 6 Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells. Bioorg Med Chem. 2013 Dec 15;21(24):7938-54.
REF 7 Structure of cIAP1-BIR3 and inhibitor
REF 8 Structural Characterization of BTK:PROTAC:cIAP Ternary Complexes: From Snapshots to Ensembles
REF 9 Structural Characterization of BTK:PROTAC:cIAP Ternary Complexes: From Snapshots to Ensembles

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