Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T63220 | Target Info | |||
| Target Name | Activated CDC42 kinase 1 (ACK-1) | ||||
| Synonyms | Tyrosine kinase non-receptor protein 2; ACK1; ACK-1 | ||||
| Target Type | Patented-recorded Target | ||||
| Gene Name | TNK2 | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: DEBROMOHYMENIALDISINE | Ligand Info | |||||
| Structure Description | Structure of the ACK1 Kinase Domain bound to Debromohymenialdisine | PDB:1U4D | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [1] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCPEAMDDF174 IREVNAMHSL 184 DHRNLIRLYG194 VVLTPPMKMV204 TELAPLGSLL214 DRLRKHQGHF224 LLGTLSRYAV 234 QVAEGMGYLE244 SKRFIHRDLA254 ARNLLLATRD264 LVKIGDFGLM274 RALPQDHYVM 286 VPFAWCAPES301 LKTRTFSHAS311 DTWMFGVTLW321 EMFTYGQEPW331 IGLNGSQILH 341 KIDKEGERLP351 RPEDCPQDIY361 NVMVQCWAHK371 PEDRPTFVAL381 RDFLLEAQ |
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| Ligand Name: L-betagamma-meATP | Ligand Info | |||||
| Structure Description | Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the CDC42-associated Tyrosine Kinase ACK1 bound to AMP-PCP | PDB:1U54 | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [1] |
| PDB Sequence |
> Chain A
QSLTCLIGEK 124 DLRLLEKLGD134 GVVRRGEWDA147 PSGKTVSVAV157 KCLAMDDFIR176 EVNAMHSLDH 186 RNLIRLYGVV196 LTPPMKMVTE206 LAPLGSLLDR216 LRKHQGHFLL226 GTLSRYAVQV 236 AEGMGYLESK246 RFIHRDLAAR256 NLLLATRDLV266 KIGDFGLMRA276 LPQNDDHVMQ 287 EHRVPFAWCA298 PESLKTRTFS308 HASDTWMFGV318 TLWEMFTYGQ328 EPWIGLNGSQ 338 ILHKIDKEGE348 RLPRPEDCPQ358 DIYNVMVQCW368 AHKPEDRPTF378 VALRDFLLEA 388 QP> Chain B LTCLIGEKDL 126 RLLEKLGDGV139 VRRGEWDAPS149 GKTVSVAVKC159 LEAMDDFIRE177 VNAMHSLDHR 187 NLIRLYGVVL197 TPPMKMVTEL207 APLGSLLDRL217 RKHQGHFLLG227 TLSRYAVQVA 237 EGMGYLESKR247 FIHRDLAARN257 LLLATRDLVK267 IGDFGLMRAL277 PQNDDHYVMQ 287 EHRKVPFAWC297 APESLKTRTF307 SHASDTWMFG317 VTLWEMFTYG327 QEPWIGLNGS 337 QILHKIDKEG347 ERLPRPEDCP357 QDIYNVMVQC367 WAHKPEDRPT377 FVALRDFLLE 387 A
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LEU132[A]
4.060
GLY133[A]
3.535
ASP134[A]
3.654
GLY138[A]
4.753
VAL140[A]
3.697
ALA156[A]
3.422
LYS158[A]
2.720
GLU177[A]
4.785
ILE190[A]
3.847
THR205[A]
3.728
GLU206[A]
2.976
LEU207[A]
3.931
ALA208[A]
3.214
GLY211[A]
4.360
SER212[A]
4.021
ASP252[A]
4.665
ARG256[A]
4.379
ASN257[A]
3.404
LEU259[A]
3.380
GLY269[A]
4.716
ASP270[A]
3.044
LEU132[B]
3.447
GLY133[B]
3.440
ASP134[B]
3.864
GLY138[B]
4.889
VAL140[B]
3.620
ALA156[B]
3.226
LYS158[B]
3.022
ILE190[B]
4.412
THR205[B]
3.934
GLU206[B]
2.867
LEU207[B]
3.633
ALA208[B]
3.206
GLY211[B]
4.505
SER212[B]
3.607
ASP252[B]
4.594
ARG256[B]
3.449
ASN257[B]
3.557
LEU259[B]
3.446
ASP270[B]
2.503
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| Ligand Name: Phosphonotyrosine | Ligand Info | |||||
| Structure Description | Co-crystal structure of ACK1 with inhibitor | PDB:4EWH | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [2] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLKPDVLS166 QPEAMDDFIR 176 EVNAMHSLDH186 RNLIRLYGVV196 LTPPMKMVTE206 LAPLGSLLDR216 LRKHQGHFLL 226 GTLSRYAVQV236 AEGMGYLESK246 RFIHRDLAAR256 NLLLATRDLV266 KIGDFGLMRA 276 LPQNDDHVMQ287 EHRKVPFAWC297 APESLKTRTF307 SHASDTWMFG317 VTLWEMFTYG 327 QEPWIGLNGS337 QILHKIDKEG347 ERLPRPEDCP357 QDIYNVMVQC367 WAHKPEDRPT 377 FVALRDFLLE387 AQP
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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 .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .B:176 or .B:249 or .B:251 or .B:275 or .B:277 or .B:282 or .B:283 or .B:285 or .B:286 or .B:287 or .B:290 or .B:305 or .B:306 or .B:307; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2-[4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-methoxyanilino]-9-methyl-5,7-dihydropyrimido[5,4-d][1,3]benzodiazepin-6-one | Ligand Info | |||||
| Structure Description | Crystal Structure Analysis of human ACK1 | PDB:6VQM | ||||
| Method | X-ray diffraction | Resolution | 2.87 Å | Mutation | No | [3] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLPEAMDD173 FIREVNAMHS 183 LDHRNLIRLY193 GVVLTPPMKM203 VTELAPLGSL213 LDRLRKHQGH223 FLLGTLSRYA 233 VQVAEGMGYL243 ESKRFIHRDL253 AARNLLLATR263 DLVKIGDFGL273 MRALPQNDDH 283 YVMQEHRKVP293 FAWCAPESLK303 TRTFSHASDT313 WMFGVTLWEM323 FTYGQEPWIG 333 LNGSQILHKI343 DKEGERLPRP353 EDCPQDIYNV363 MVQCWAHKPE373 DRPTFVALRD 383 FLLEAQP
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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 .R7P or .R7P2 or .R7P3 or :3R7P;style chemicals stick;color identity;select .A:131 or .A:132 or .A:133 or .A:134 or .A:135 or .A:140 or .A:142 or .A:156 or .A:158 or .A:181 or .A:190 or .A:205 or .A:206 or .A:207 or .A:208 or .A:209 or .A:210 or .A:211 or .A:212 or .A:259 or .A:269 or .A:270; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LYS131
3.967
LEU132
3.622
GLY133
3.985
ASP134
3.918
GLY135
3.707
VAL140
3.632
ARG142
4.947
ALA156
3.747
LYS158
4.075
MET181
4.927
ILE190
3.561
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| Ligand Name: (R)-5-Chloro-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)pyrimidine-2,4-diamine | Ligand Info | |||||
| Structure Description | Structure of Ack1 kinase in complex with a selective inhibitor | PDB:7KP6 | ||||
| Method | X-ray diffraction | Resolution | 1.79 Å | Mutation | No | [4] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLPEAMDD173 FIREVNAMHS 183 LDHRNLIRLY193 GVVLTPPMKM203 VTELAPLGSL213 LDRLRKHQGH223 FLLGTLSRYA 233 VQVAEGMGYL243 ESKRFIHRDL253 AARNLLLATR263 DLVKIGDFGL273 MRALPQNDDH 283 YVMQEHRKVP293 FAWCAPESLK303 TRTFSHASDT313 WMFGVTLWEM323 FTYGQEPWIG 333 LNGSQILHKI343 DKEGERLPRP353 EDCPQDIYNV363 MVQCWAHKPE373 DRPTFVALRD 383 FLLEAQPT
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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 .WTP or .WTP2 or .WTP3 or :3WTP;style chemicals stick;color identity;select .A:131 or .A:132 or .A:133 or .A:134 or .A:135 or .A:140 or .A:156 or .A:158 or .A:190 or .A:205 or .A:206 or .A:207 or .A:208 or .A:209 or .A:210 or .A:211 or .A:212 or .A:216 or .A:256 or .A:257 or .A:259 or .A:269 or .A:270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LYS131
4.601
LEU132
2.319
GLY133
2.537
ASP134
2.659
GLY135
3.157
VAL140
2.329
ALA156
3.006
LYS158
2.801
ILE190
2.721
THR205
2.907
GLU206
2.389
LEU207
2.628
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| Ligand Name: N~3~-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-N~6~-(4-piperazin-1-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine | Ligand Info | |||||
| Structure Description | Crystal Structure of Ack1 with compound T74 | PDB:3EQR | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [5] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLKPEAMD172 DFIREVNAMH 182 SLDHRNLIRL192 YGVVLTPPMK202 MVTELAPLGS212 LLDRLRKHQG222 HFLLGTLSRY 232 AVQVAEGMGY242 LESKRFIHRD252 LAARNLLLAT262 RDLVKIGDFG272 LMRALPQNDD 282 HYVMQEHRKV292 PFAWCAPESL302 KTRTFSHASD312 TWMFGVTLWE322 MFTYGQEPWI 332 GLNGSQILHK342 IDKEGERLPR352 PEDCPQDIYN362 VMVQCWAHKP372 EDRPTFVALR 382 DFLLEAQPTD392
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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 .T74 or .T742 or .T743 or :3T74;style chemicals stick;color identity;select .A:131 or .A:132 or .A:133 or .A:134 or .A:135 or .A:140 or .A:156 or .A:157 or .A:158 or .A:177 or .A:181 or .A:190 or .A:203 or .A:205 or .A:206 or .A:207 or .A:208 or .A:209 or .A:210 or .A:211 or .A:212 or .A:256 or .A:257 or .A:259 or .A:268 or .A:269 or .A:270 or .A:271; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LYS131
4.517
LEU132
3.099
GLY133
4.311
ASP134
3.385
GLY135
4.066
VAL140
3.635
ALA156
3.372
VAL157
3.746
LYS158
3.221
GLU177
3.320
MET181
3.756
ILE190
3.697
MET203
3.946
THR205
2.999
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| Ligand Name: N-(2,6-dimethylphenyl)-4-(2-ethoxyphenoxy)-2-({4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide | Ligand Info | |||||
| Structure Description | Crystal Structure of Ack1 with compound T95 | PDB:3EQP | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [5] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLQPEAMD172 DFIREVNAMH 182 SLDHRNLIRL192 YGVVLTPPMK202 MVTELAPLGS212 LLDRLRKHQG222 HFLLGTLSRY 232 AVQVAEGMGY242 LESKRFIHRD252 LAARNLLLAT262 RDLVKIGDFG272 LMRALPQNDD 282 HYVMQEHRKV292 PFAWCAPESL302 KTRTFSHASD312 TWMFGVTLWE322 MFTYGQEPWI 332 GLNGSQILHK342 IDKEGERLPR352 PEDCPQDIYN362 VMVQCWAHKP372 EDRPTFVALR 382 DFLLEAQPTD392
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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 .T95 or .T952 or .T953 or :3T95;style chemicals stick;color identity;select .B:132 or .B:133 or .B:137 or .B:140 or .B:156 or .B:157 or .B:158 or .B:177 or .B:190 or .B:203 or .B:205 or .B:206 or .B:207 or .B:208 or .B:209 or .B:210 or .B:211 or .B:212 or .B:256 or .B:257 or .B:258 or .B:259 or .B:269 or .B:270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU132
3.411
GLY133
3.573
PHE137
3.762
VAL140
3.637
ALA156
3.514
VAL157
4.130
LYS158
3.437
GLU177
2.974
ILE190
3.402
MET203
3.971
THR205
3.212
GLU206
3.777
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| Ligand Name: N-[3-[7-[[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide | Ligand Info | |||||
| Structure Description | Crystal structure of ACK1 with compound 10d | PDB:5ZXB | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [6] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGV139 VRRGEWDAPS149 GKTVSVAVKC159 LAMDDFIREV178 NAMHSLDHRN 188 LIRLYGVVLT198 PPMKMVTELA208 PLGSLLDRLR218 KHQGHFLLGT228 LSRYAVQVAE 238 GMGYLESKRF248 IHRDLAARNL258 LLATRDLVKI268 GDFPFAWCAP299 ESLKTRTFSH 309 ASDTWMFGVT319 LWEMFTYGQE329 PWIGLNGSQI339 LHKIDKEGER349 LPRPEDCPQD 359 IYNVMVQCWA369 HKPEDRPTFV379 ALRDFLLEAQ389
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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 .9KO or .9KO2 or .9KO3 or :39KO;style chemicals stick;color identity;select .A:131 or .A:132 or .A:140 or .A:156 or .A:157 or .A:158 or .A:177 or .A:180 or .A:181 or .A:184 or .A:189 or .A:190 or .A:203 or .A:205 or .A:206 or .A:207 or .A:208 or .A:209 or .A:210 or .A:211 or .A:212 or .A:243 or .A:248 or .A:250 or .A:259 or .A:268 or .A:269 or .A:270 or .A:271; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LYS131
4.986
LEU132
3.570
VAL140
3.732
ALA156
3.548
VAL157
3.969
LYS158
3.501
GLU177
3.115
ALA180
4.863
MET181
2.967
LEU184
3.399
LEU189
4.041
ILE190
3.947
MET203
4.236
THR205
3.238
GLU206
3.207
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| Ligand Name: 6-{4-[2-(Dimethylamino)ethoxy]phenyl}-N-(1,3-Dithiolan-2-Ylmethyl)-5-Phenyl-7h-Pyrrolo[2,3-D]pyrimidin-4-Amine | Ligand Info | |||||
| Structure Description | Co-crystal structure of ACK1 with inhibitor | PDB:4EWH | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [2] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLKPDVLS166 QPEAMDDFIR 176 EVNAMHSLDH186 RNLIRLYGVV196 LTPPMKMVTE206 LAPLGSLLDR216 LRKHQGHFLL 226 GTLSRYAVQV236 AEGMGYLESK246 RFIHRDLAAR256 NLLLATRDLV266 KIGDFGLMRA 276 LPQNDDHVMQ287 EHRKVPFAWC297 APESLKTRTF307 SHASDTWMFG317 VTLWEMFTYG 327 QEPWIGLNGS337 QILHKIDKEG347 ERLPRPEDCP357 QDIYNVMVQC367 WAHKPEDRPT 377 FVALRDFLLE387 AQP
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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 .T77 or .T772 or .T773 or :3T77;style chemicals stick;color identity;select .B:132 or .B:133 or .B:134 or .B:135 or .B:140 or .B:142 or .B:156 or .B:158 or .B:190 or .B:205 or .B:206 or .B:207 or .B:208 or .B:209 or .B:210 or .B:211 or .B:212 or .B:219 or .B:256 or .B:257 or .B:259 or .B:269 or .B:270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU132
3.283
GLY133
3.630
ASP134
3.561
GLY135
3.998
VAL140
3.858
ARG142
4.907
ALA156
3.501
LYS158
4.238
ILE190
4.212
THR205
4.111
GLU206
3.389
LEU207
3.770
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| Ligand Name: Cis-3-[8-Amino-1-(4-Phenoxyphenyl)imidazo[1,5-A]pyrazin-3-Yl]cyclobutanol | Ligand Info | |||||
| Structure Description | ACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol | PDB:4ID7 | ||||
| Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [7] |
| PDB Sequence |
LTCLIGEKDL
126 RLLEKLGDGS136 FGVVRRGEWD146 APSGKTVSVA156 VKCLKPPEAM171 DDFIREVNAM 181 HSLDHRNLIR191 LYGVVLTPPM201 KMVTELAPLG211 SLLDRLRKHQ221 GHFLLGTLSR 231 YAVQVAEGMG241 YLESKRFIHR251 DLAARNLLLA261 TRDLVKIGDF271 GLMRALPQND 281 DHYVMQEHRK291 VPFAWCAPES301 LKTRTFSHAS311 DTWMFGVTLW321 EMFTYGQEPW 331 IGLNGSQILH341 KIDKEGERLP351 RPEDCPQDIY361 NVMVQCWAHK371 PEDRPTFVAL 381 RDFLLEAQ
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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 .1G0 or .1G02 or .1G03 or :31G0;style chemicals stick;color identity;select .A:132 or .A:133 or .A:140 or .A:156 or .A:158 or .A:177 or .A:181 or .A:190 or .A:191 or .A:192 or .A:203 or .A:205 or .A:206 or .A:207 or .A:208 or .A:211 or .A:212 or .A:259 or .A:269 or .A:270 or .A:271; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU132
3.923
GLY133
4.240
VAL140
3.593
ALA156
3.596
LYS158
3.426
GLU177
3.928
MET181
3.526
ILE190
3.424
ARG191
4.996
LEU192
3.940
MET203
3.763
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| Ligand Name: Phosphoaminophosphonic acid-guanylate ester | Ligand Info | |||||
| Structure Description | CDC42/ACK GTPASE-BINDING DOMAIN COMPLEX | PDB:1CF4 | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | No | [8] |
| PDB Sequence |
GSGLSAQDIS
511 QPLQNSFIHT521 GHGDSDPRHC531 WGFPDRIDEL541 YLGN
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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 .GNP or .GNP2 or .GNP3 or :3GNP;style chemicals stick;color identity;select .B:532 or .B:535 or .B:537 or .B:543; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1. J Biol Chem. 2004 Oct 15;279(42):44039-45. | ||||
| REF 2 | Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6212-7 | ||||
| REF 3 | Crystal Structure Analysis of human ACK1 | ||||
| REF 4 | Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun. 2022 Nov 14;13(1):6929. | ||||
| REF 5 | Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6352-6. | ||||
| REF 6 | First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia. J Med Chem. 2018 Sep 27;61(18):8353-8373. | ||||
| REF 7 | Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors. Bioorg Med Chem Lett. 2013 Feb 15;23(4):979-84. | ||||
| REF 8 | Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. Nature. 1999 May 27;399(6734):384-8. | ||||
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