Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T56418 | Target Info | |||
| Target Name | ALK tyrosine kinase receptor (ALK) | ||||
| Synonyms | CD246; Anaplastic lymphoma kinase | ||||
| Target Type | Successful Target | ||||
| Gene Name | ALK | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Crizotinib | Ligand Info | |||
| Canonical SMILES | CC(C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N | ||||
| InChI | 1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 | ||||
| InChIKey | KTEIFNKAUNYNJU-GFCCVEGCSA-N | ||||
| PubChem Compound ID | 11626560 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 4ANQ Structure of G1269A Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 1.76 Å | Mutation | Yes | [1] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GAFGEVYEGQ1134 VPLQVAVKTL1152 PEVCSEQDEL 1162 DFLMEALIIS1172 KFNHQNIVRC1182 IGVSLQSLPR1192 FILLELMAGG1202 DLKSFLRETR 1212 PRPSQPSSLA1222 MLDLLHVARD1232 IACGCQYLEE1242 NHFIHRDIAA1252 RNCLLTCPGP 1262 GRVAKIADFG1272 MARDIYRGGC1288 AMLPVKWMPP1298 EAFMEGIFTS1308 KTDTWSFGVL 1318 LWEIFSLGYM1328 PYPSKSNQEV1338 LEFVTSGGRM1348 DPPKNCPGPV1358 YRIMTQCWQH 1368 QPEDRPNFAI1378 ILERIEYCTQ1388 DPDVINTALP1398 IEYG
|
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LEU1122
3.637
VAL1130
3.972
ALA1148
3.378
LYS1150
4.222
VAL1180
4.457
LEU1196
3.672
GLU1197
2.965
LEU1198
3.893
MET1199
2.895
ALA1200
3.328
|
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| PDB ID: 4ANS Structure of L1196M,G1269A Double Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | Yes | [2] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GAFGEVYEGQ1134 VPLQVAVKTL1152 PEVCSEQDEL 1162 DFLMEALIIS1172 KFNHQNIVRC1182 IGVSLQSLPR1192 FILMELMAGG1202 DLKSFLRETR 1212 PRPSQPSSLA1222 MLDLLHVARD1232 IACGCQYLEE1242 NHFIHRDIAA1252 RNCLLTCPGP 1262 GRVAKIADFG1272 MARDIYRGGC1288 AMLPVKWMPP1298 EAFMEGIFTS1308 KTDTWSFGVL 1318 LWEIFSLGYM1328 PYPSKSNQEV1338 LEFVTSGGRM1348 DPPKNCPGPV1358 YRIMTQCWQH 1368 QPEDRPNFAI1378 ILERIEYCTQ1388 DPDVINTALP1398 IEYG
|
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|
|
LEU1122
3.667
GLY1123
4.993
VAL1130
3.979
ALA1148
3.386
LYS1150
4.234
VAL1180
4.476
MET1196
3.481
GLU1197
3.099
LEU1198
3.932
MET1199
2.940
ALA1200
3.390
|
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| PDB ID: 2YFX Structure of L1196M Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [1] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GAFGEVYEGQ1134 VPLQVAVKTL1152 PEVCSEQDEL 1162 DFLMEALIIS1172 KFNHQNIVRC1182 IGVSLQSLPR1192 FILMELMAGG1202 DLKSFLRETR 1212 PRPSQPSSLA1222 MLDLLHVARD1232 IACGCQYLEE1242 NHFIHRDIAA1252 RNCLLTCPGP 1262 GRVAKIGDFG1272 MARDIYRGGC1288 AMLPVKWMPP1298 EAFMEGIFTS1308 KTDTWSFGVL 1318 LWEIFSLGYM1328 PYPSKSNQEV1338 LEFVTSGGRM1348 DPPKNCPGPV1358 YRIMTQCWQH 1368 QPEDRPNFAI1378 ILERIEYCTQ1388 DPDVINTALP1398 IEY
|
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|
|
LEU1122
3.566
VAL1130
4.063
ALA1148
3.489
LYS1150
4.107
VAL1180
4.166
MET1196
3.477
GLU1197
3.071
LEU1198
3.947
MET1199
2.918
ALA1200
3.263
|
|||||
| PDB ID: 5AAC Structure of C1156Y Mutant Human Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [3] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGEVYEGQV1135 PLQVAVKTLP1153 EVYSEQDELD 1163 FLMEALIISK1173 FNHQNIVRCI1183 GVSLQSLPRF1193 ILLELMAGGD1203 LKSFLRETRP 1213 RPSQPSSLAM1223 LDLLHVARDI1233 ACGCQYLEEN1243 HFIHRDIAAR1253 NCLLTCPGPG 1263 RVAKIGDFGM1273 ARDIYRGGCA1289 MLPVKWMPPE1299 AFMEGIFTSK1309 TDTWSFGVLL 1319 WEIFSLGYMP1329 YPSKSNQEVL1339 EFVTSGGRMD1349 PPKNCPGPVY1359 RIMTQCWQHQ 1369 PEDRPNFAII1379 LERIEYCTQD1389 PDVINTALPI1399 EYG
|
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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 .VGH or .VGH2 or .VGH3 or :3VGH;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1180 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1201 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU1122
3.609
GLY1123
4.296
VAL1130
3.882
ALA1148
3.564
LYS1150
3.828
VAL1180
4.193
LEU1196
3.812
GLU1197
3.000
LEU1198
3.939
MET1199
2.906
|
|||||
| PDB ID: 5AAA Structure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 1.73 Å | Mutation | Yes | [3] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGAFGEVYE1132 GQVPLQVAVK1150 TLPEVCSEQD 1160 ELDFLMEALI1170 ISKFNHQNIV1180 RCIGVSLQSL1190 PRFILLEFMA1200 GGDLKSFLRE 1210 TRPRPSQPSS1220 LAMLDLLHVA1230 RDIACGCQYL1240 EENHFIHRDI1250 AARNCLLTCP 1260 GPGRVAKIGD1270 FGMARDIYRG1286 GCAMLPVKWM1296 PPEAFMEGIF1306 TSKTDTWSFG 1316 VLLWEIFSLG1326 YMPYPSKSNQ1336 EVLEFVTSGG1346 RMDPPKNCPG1356 PVYRIMTQCW 1366 QHQPEDRPNF1376 AIILERIEYC1386 TQDPDVINTA1396 LPIEY
|
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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 .VGH or .VGH2 or .VGH3 or :3VGH;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1180 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1201 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU1122
3.817
GLY1123
4.524
VAL1130
3.973
ALA1148
3.422
LYS1150
4.078
VAL1180
4.145
LEU1196
3.742
GLU1197
3.039
PHE1198
3.887
MET1199
2.908
|
|||||
| PDB ID: 2XP2 Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib (PF-02341066) | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [4] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GAFGEVYEGQ1134 VSPLQVAVKT1151 LPEVCSEQDE 1161 LDFLMEALII1171 SKFNHQNIVR1181 CIGVSLQSLP1191 RFILLELMAG1201 GDLKSFLRET 1211 RPRPSQSLAM1223 LDLLHVARDI1233 ACGCQYLEEN1243 HFIHRDIAAR1253 NCLLTCPGPG 1263 RVAKIGDFGM1273 ARDIYRAMLP1292 VKWMPPEAFM1302 EGIFTSKTDT1312 WSFGVLLWEI 1322 FSLGYMPYPS1332 KSNQEVLEFV1342 TSGGRMDPPK1352 NCPGPVYRIM1362 TQCWQHQPED 1372 RPNFAIILER1382 IEYCTQDPDV1392 INTALPIEY
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .VGH or .VGH2 or .VGH3 or :3VGH;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1180 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1201 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU1122
3.796
GLY1123
4.670
VAL1130
3.965
ALA1148
3.466
LYS1150
4.176
VAL1180
4.333
LEU1196
3.680
GLU1197
3.026
LEU1198
3.903
MET1199
2.895
|
|||||
| PDB ID: 5AAB Structure of C1156Y,L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [3] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGGEVYEGQ1134 VPLQVAVKTL1152 PEVYSEQDEL 1162 DFLMEALIIS1172 KFNHQNIVRC1182 IGVSLQSLPR1192 FILLEFMAGG1202 DLKSFLRETR 1212 PRPSQPSSLA1222 MLDLLHVARD1232 IACGCQYLEE1242 NHFIHRDIAA1252 RNCLLTCPGP 1262 GRVAKIGDFG1272 MARDIYRGGC1288 AMLPVKWMPP1298 EAFMEGIFTS1308 KTDTWSFGVL 1318 LWEIFSLGYM1328 PYPSKSNQEV1338 LEFVTSGGRM1348 DPPKNCPGPV1358 YRIMTQCWQH 1368 QPEDRPNFAI1378 ILERIEYCTQ1388 DPDVINTALP1398 IEYG
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .VGH or .VGH2 or .VGH3 or :3VGH;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1180 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1201 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU1122
3.631
GLY1123
4.608
VAL1130
3.970
ALA1148
3.451
LYS1150
3.849
VAL1180
4.178
LEU1196
3.812
GLU1197
3.019
PHE1198
3.921
MET1199
2.959
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87. | ||||
| REF 2 | Structure of L1196M,G1269A Double Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib | ||||
| REF 3 | Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med. 2016 Jan 7;374(1):54-61. | ||||
| REF 4 | Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63. | ||||
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