Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T31309 Target Info
Target Name Apoptosis regulator Bcl-2 (BCL-2)
Synonyms Bcl-2
Target Type Successful Target
Gene Name BCL2
Biochemical Class B-cell lymphoma Bcl-2
UniProt ID
BCL2_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: ABT-263 Ligand Info
Structure Description Bcl_2-Navitoclax (ABT-263) Complex PDB:4LVT
Method X-ray diffraction Resolution 2.05 Å Mutation Yes [1]
PDB Sequence
YDNREIVMKY
16
IHYKLSQRGY
26
EWDASEVVHL
92
TLRQAGDDFS
102
RRYRRDFAEM
112

SSQLHLTPFT
122
ARGRFATVVE
132
ELFRDGVNWG
142
RIVAFFEFGG
152
VMCVESVNRE
162

MSPLVDNIAL
172
WMTEYLNRHL
182
HTWIQDNGGW
192
DAFVELYGP
Residue
Distance (Å)
ALA97
3.618
ASP100
3.648
PHE101
3.508
ARG104
3.413
TYR105
3.363
ASP108
3.449
PHE109
3.665
MET112
3.730
VAL130
3.803
GLU133
3.975
LEU134
3.729
ASN140
3.557
Residue
Distance (Å)
TRP141
3.306
GLY142
3.140
ARG143
3.694
VAL145
3.419
ALA146
3.279
GLU149
3.939
PHE150
3.754
VAL153
3.849
PHE195
3.010
LEU198
3.308
TYR199
3.297
GLY200
4.813
Ligand Name: 4-(4-{[4-(4-Chlorophenyl)-5,6-Dihydro-2h-Pyran-3-Yl]methyl}piperazin-1-Yl)-N-{[3-Nitro-4-(Tetrahydro-2h-Pyran-4-Ylamino)phenyl]sulfonyl}benzamide Ligand Info
Structure Description Bcl_2-Navitoclax Analog (without Thiophenyl) Complex PDB:4LXD
Method X-ray diffraction Resolution 1.90 Å Mutation Yes [1]
PDB Sequence
RTGYDNREIV
13
MKYIHYKLSQ
23
RGYEWDAGSE
88
VVHLTLRQAG
98
DDFSRRYRRD
108

FAEMSSQLHL
118
TPFTARGRFA
128
TVVEELFRDG
138
VNWGRIVAFF
148
EFGGVMCVES
158

VNREMSPLVD
168
NIALWMTEYL
178
NRHLHTWIQD
188
NGGWDAFVEL
198
YGP
Residue
Distance (Å)
ALA97
3.599
ASP100
3.327
PHE101
3.729
TYR105
3.348
ASP108
3.701
PHE109
3.702
MET112
3.687
VAL130
3.641
GLU133
3.567
LEU134
3.585
ASN140
3.349
Residue
Distance (Å)
TRP141
3.611
GLY142
2.991
ARG143
3.672
VAL145
3.384
ALA146
3.336
GLU149
4.057
PHE150
3.800
VAL153
3.915
PHE195
3.723
TYR199
3.404
Ligand Name: 4-[4-({4'-Chloro-3-[2-(Dimethylamino)ethoxy]biphenyl-2-Yl}methyl)piperazin-1-Yl]-2-(1h-Indol-5-Yloxy)-N-({3-Nitro-4-[(Tetrahydro-2h-Pyran-4-Ylmethyl)amino]phenyl}sulfonyl)benzamide Ligand Info
Structure Description Bcl_2-Navitoclax Analog (with Indole) Complex PDB:4MAN
Method X-ray diffraction Resolution 2.07 Å Mutation No [1]
PDB Sequence
GYDNREIVMK
15
YIHYKLSQRG
25
YEEVVHLTLR
95
QAGDDFSRRY
105
RRDFAEMSSQ
115

LHLTPFTARG
125
RFATVVEELF
135
RDGVNWGRIV
145
AFFEFGGVMC
155
VESVNREMSP
165

LVDNIALWMT
175
EYLNRHLHTW
185
IQDNGGWDAF
195
VELYGP
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .1Y1 or .1Y12 or .1Y13 or :31Y1;style chemicals stick;color identity;select .A:93 or .A:96 or .A:97 or .A:98 or .A:100 or .A:101 or .A:104 or .A:105 or .A:108 or .A:109 or .A:112 or .A:130 or .A:133 or .A:134 or .A:140 or .A:141 or .A:142 or .A:143 or .A:145 or .A:146 or .A:147 or .A:149 or .A:150 or .A:153 or .A:195 or .A:199; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
THR93
4.228
GLN96
4.063
ALA97
2.522
GLY98
4.250
ASP100
2.793
PHE101
3.436
ARG104
3.554
TYR105
2.612
ASP108
2.706
PHE109
3.386
MET112
2.996
VAL130
2.869
GLU133
3.209
Residue
Distance (Å)
LEU134
3.196
ASN140
2.700
TRP141
3.347
GLY142
3.144
ARG143
2.960
VAL145
3.016
ALA146
2.317
PHE147
4.375
GLU149
3.997
PHE150
3.177
VAL153
4.361
PHE195
3.740
TYR199
3.472
Ligand Name: XD30VB6Drt Ligand Info
Structure Description Crystal structure of Bcl-2 in complex with prodrug ABBV-167 PDB:7LHB
Method X-ray diffraction Resolution 2.07 Å Mutation Yes [2]
PDB Sequence
YDNREIVMKY
18
IHYKLSQKGY
28
EWSEVVHLTL
97
RQAGDDFSRR
107
YRRDFAEMSS
117

QLHLTPFTAR
127
GRFATVVEEL
137
FRDGVNWGRI
147
VAFFEFGGVM
157
CVESVNREMS
167

PLVDNIALWM
177
TEYLNRHLHT
187
WIQDNGGWDA
197
FVELYGP
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .XZD or .XZD2 or .XZD3 or :3XZD;style chemicals stick;color identity;select .A:99 or .A:100 or .A:103 or .A:104 or .A:107 or .A:108 or .A:111 or .A:112 or .A:115 or .A:133 or .A:136 or .A:137 or .A:143 or .A:144 or .A:145 or .A:146 or .A:148 or .A:149 or .A:152 or .A:153 or .A:156 or .A:198 or .A:202; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLN99
3.989
ALA100
3.209
ASP103
2.799
PHE104
3.733
ARG107
3.056
TYR108
3.264
ASP111
3.516
PHE112
3.286
MET115
3.732
VAL133
4.137
GLU136
3.653
LEU137
3.797
Residue
Distance (Å)
ASN143
3.279
TRP144
3.244
GLY145
3.017
ARG146
3.730
VAL148
3.268
ALA149
3.529
GLU152
3.661
PHE153
3.692
VAL156
3.632
PHE198
3.644
TYR202
3.476
Ligand Name: 3-Nitro-N-{4-[2-(2-phenylethyl)-1,3-benzothiazol-5-YL]benzoyl}-4-{[2-(phenylsulfanyl)ethyl]amino}benzenesulfonamide Ligand Info
Structure Description Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand PDB:1YSW
Method Solution NMR Resolution N.A. Mutation No [3]
PDB Sequence
HAGRTGYDNR
10
EIVMKYIHYK
20
LSQRGYEWDA
30
GDDVEENRTE
40
APEGTESEVV
90

HLTLRQAGDD
100
FSRRYRRDFA
110
EMSSQLHLTP
120
FTARGRFATV
130
VEELFRDGVN
140

WGRIVAFFEF
150
GGVMCVESVN
160
REMSPLVDNI
170
ALWMTEYLNR
180
HLHTWIQDNG
190

GWDAFVELYG
200
PSMR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .43B or .43B2 or .43B3 or :343B;style chemicals stick;color identity;select .A:96 or .A:97 or .A:98 or .A:100 or .A:101 or .A:104 or .A:105 or .A:108 or .A:109 or .A:112 or .A:130 or .A:131 or .A:133 or .A:134 or .A:141 or .A:142 or .A:143 or .A:144 or .A:145 or .A:146 or .A:147 or .A:149 or .A:150 or .A:153 or .A:195 or .A:199; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLN96
4.141
ALA97
2.259
GLY98
4.211
ASP100
2.113
PHE101
1.893
ARG104
3.761
TYR105
2.181
ASP108
4.071
PHE109
2.265
MET112
1.913
VAL130
2.540
VAL131
3.635
GLU133
2.410
Residue
Distance (Å)
LEU134
2.242
TRP141
2.985
GLY142
1.686
ARG143
2.337
ILE144
4.367
VAL145
1.981
ALA146
1.918
PHE147
4.333
GLU149
2.565
PHE150
2.429
VAL153
2.605
PHE195
2.604
TYR199
2.279
Click to View More Binding Site Information of This Target and Ligand Pair
Ligand Name: N-[(4-{[1,1-Dimethyl-2-(Phenylthio)ethyl]amino}-3-Nitrophenyl)sulfonyl]-4-(4,4-Dimethylpiperidin-1-Yl)benzamide Ligand Info
Structure Description Solution structure of the anti-apoptotic protein Bcl-2 in complex with an acyl-sulfonamide-based ligand PDB:2O22
Method Solution NMR Resolution N.A. Mutation No [4]
PDB Sequence
HAGRTGYDNR
10
EIVMKYIHYK
20
LSQRGYEWDA
30
GDDVEENRTE
40
APEGTESEVV
90

HLTLRQAGDD
100
FSRRYRRDFA
110
EMSSQLHLTP
120
FTARGRFATV
130
VEELFRDGVN
140

WGRIVAFFEF
150
GGVMCVESVN
160
REMSPLVDNI
170
ALWMTEYLNR
180
HLHTWIQDNG
190

GWDAFVELYG
200
PSMR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LIU or .LIU2 or .LIU3 or :3LIU;style chemicals stick;color identity;select .A:93 or .A:96 or .A:97 or .A:98 or .A:100 or .A:101 or .A:102 or .A:104 or .A:105 or .A:108 or .A:109 or .A:112 or .A:134 or .A:140 or .A:141 or .A:142 or .A:143 or .A:145 or .A:146 or .A:150 or .A:195 or .A:199; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
THR93
4.508
GLN96
4.882
ALA97
2.524
GLY98
4.427
ASP100
2.641
PHE101
1.766
SER102
4.711
ARG104
2.851
TYR105
2.020
ASP108
1.937
PHE109
1.932
Residue
Distance (Å)
MET112
2.884
LEU134
2.424
ASN140
4.361
TRP141
2.529
GLY142
1.572
ARG143
2.369
VAL145
2.060
ALA146
2.026
PHE150
4.627
PHE195
2.276
TYR199
1.839
Ligand Name: 1-(2-{[(3S)-3-(aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-4-chloro-5-methyl-N,N-diphenyl-1H-pyrazole-3-carboxamide Ligand Info
Structure Description Crystal Structure of Chimaeric Bcl2-xL and Phenyl Tetrahydroisoquinoline Amide Complex PDB:2W3L
Method X-ray diffraction Resolution 2.10 Å Mutation No [5]
PDB Sequence
YDNREIVMKY
18
IHYKLSQRGY
28
EWDASEVVHK
54
TLREAGDDFS
64
RRYRRDFAEM
74

SSGLHLTPFT
84
ARGRFATVVE
94
ELFRDGVNWG
104
RIVAFFEFGG
114
VMCVESVNRE
124

MSPLVDNIAL
134
WMTEYLNRHL
144
HTWIQDNGGW
154
DAFVELYGPS
164
M
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DRO or .DRO2 or .DRO3 or :3DRO;style chemicals stick;color identity;select .A:63 or .A:67 or .A:70 or .A:71 or .A:74 or .A:88 or .A:92 or .A:95 or .A:96 or .A:104 or .A:105 or .A:108 or .A:109 or .A:112; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
PHE63
3.399
TYR67
3.439
ASP70
3.386
PHE71
3.840
MET74
3.235
ARG88
4.321
VAL92
3.621
Residue
Distance (Å)
GLU95
3.515
LEU96
3.581
GLY104
3.926
ARG105
4.170
ALA108
3.266
PHE109
4.651
PHE112
3.663
Ligand Name: 4-(4-Benzyl-4-Methoxypiperidin-1-Yl)-N-[(4-{[1,1-Dimethyl-2-(Phenylthio)ethyl]amino}-3-Nitrophenyl)sulfonyl]benzamide Ligand Info
Structure Description Solution structure of the anti-apoptotic protein Bcl-2 in complex with an acyl-sulfonamide-based ligand PDB:2O2F
Method Solution NMR Resolution N.A. Mutation No [4]
PDB Sequence
GYDNREIVMK
15
YIHYKLSQRG
25
YEWDEVVHLT
93
LRQAGDDFSR
103
RYRRDFAEMS
113

SQLHLTPFTA
123
RGRFATVVEE
133
LFRDGVNWGR
143
IVAFFEFGGV
153
MCVESVNREM
163

SPLVDNIALW
173
MTEYLNRHLH
183
TWIQDNGGWD
193
AFVELYGP
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LI0 or .LI02 or .LI03 or :3LI0;style chemicals stick;color identity;select .A:96 or .A:97 or .A:98 or .A:100 or .A:101 or .A:104 or .A:105 or .A:108 or .A:109 or .A:112 or .A:116 or .A:130 or .A:131 or .A:133 or .A:134 or .A:140 or .A:141 or .A:142 or .A:143 or .A:145 or .A:146 or .A:147 or .A:149 or .A:150 or .A:151 or .A:195 or .A:199; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLN96
3.650
ALA97
2.265
GLY98
4.335
ASP100
2.567
PHE101
1.652
ARG104
2.515
TYR105
2.250
ASP108
2.156
PHE109
2.072
MET112
1.840
LEU116
4.909
VAL130
2.252
VAL131
4.245
GLU133
3.577
Residue
Distance (Å)
LEU134
2.314
ASN140
4.276
TRP141
2.210
GLY142
1.614
ARG143
2.047
VAL145
2.079
ALA146
2.221
PHE147
2.660
GLU149
3.685
PHE150
2.110
GLY151
4.977
PHE195
3.041
TYR199
2.167
References  Top
REF 1 ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.
REF 2 Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers. Mol Cancer Ther. 2021 Jun;20(6):999-1008.
REF 3 An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81.
REF 4 Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007 Feb 22;50(4):641-62.
REF 5 Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors. Bioorg Med Chem Lett. 2009 Jan 1;19(1):230-3.

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