Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T40474 Target Info
Target Name Proto-oncogene c-Met (MET)
Synonyms Tyrosine-protein kinase Met; Scatter factor receptor; SF receptor; Met proto-oncogene tyrosine kinase; Hepatocyte growth factor receptor; HGF/SF receptor; HGF-SF receptor; HGF receptor; C-met; C-Met receptor tyrosine kinase
Target Type Successful Target
Gene Name MET
Biochemical Class Kinase
UniProt ID
MET_HUMAN
Ligand General Information  Top
Ligand Name XL880 Ligand Info
Canonical SMILES COC1=CC2=C(C=CN=C2C=C1OCCCN3CCOCC3)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F
InChI 1S/C34H34F2N4O6/c1-43-30-20-25-27(21-31(30)45-16-2-13-40-14-17-44-18-15-40)37-12-9-28(25)46-29-8-7-24(19-26(29)36)39-33(42)34(10-11-34)32(41)38-23-5-3-22(35)4-6-23/h3-9,12,19-21H,2,10-11,13-18H2,1H3,(H,38,41)(H,39,42)
InChIKey CXQHYVUVSFXTMY-UHFFFAOYSA-N
PubChem Compound ID 42642645
Drug Binding Sites of Target  Top
PDB ID: 6SDC      Crystal structure of D1228V cMET bound by foretinib
Method X-ray diffraction Resolution 1.67 Å Mutation Yes [1]
PDB Sequence
HIDLSALNPE
1061
LVQAVQHVVI
1071
GPSSLIVHFN
1081
EVIGRGHFGC
1091
VYHGTLLDGK
1103

KIHCAVKSLN
1113
RITDIGEVSQ
1123
FLTEGIIMKD
1133
FSHPNVLSLL
1143
GICLRSEGSP
1153

LVVLPYMKHG
1163
DLRNFIRNHN
1175
PTVKDLIGFG
1185
LQVAKGMKYL
1195
ASKKFVHRDL
1205

AARNCMLDEK
1215
FTVKVADFGL
1225
ARVMYDKEYY
1235
SVAKLPVKWM
1250
ALESLQTQKF
1260

TTKSDVWSFG
1270
VLLWELMTRG
1280
APPYPDVNTF
1290
DITVYLLQGR
1300
RLLQPEYCPD
1310

PLYEVMLKCW
1320
HPKAEMRPSF
1330
SELVSRISAI
1340
FSTFIG
Residue
Distance (Å)
ILE1084
3.144
GLY1085
4.850
VAL1092
3.249
ALA1108
3.313
LYS1110
2.776
GLU1127
3.346
GLY1128
4.012
MET1131
3.338
PHE1134
3.602
VAL1139
3.869
LEU1140
3.758
VAL1155
4.658
LEU1157
3.656
PRO1158
3.296
TYR1159
3.335
MET1160
2.940
Residue
Distance (Å)
LYS1161
3.697
HIS1162
4.250
GLY1163
3.724
ASN1171
4.205
LEU1195
3.052
PHE1200
3.699
HIS1202
3.577
MET1211
3.395
VAL1220
3.352
ALA1221
3.520
ASP1222
2.846
PHE1223
3.354
GLY1224
4.713
ALA1226
4.451
VAL1228
4.638
TYR1230
4.107
PDB ID: 6SD9      Crystal structure of wild-type cMET bound by foretinib
Method X-ray diffraction Resolution 2.35 Å Mutation No [1]
PDB Sequence
LVQAVQHVVI
1071
GPSSLIVHFN
1081
EVIGRGHFGC
1091
VYHGTLLDND
1101
GKKIHCAVKS
1111

LNREVSQFLT
1126
EGIIMKDFSH
1136
PNVLSLLGIC
1146
LPLVVLPYMK
1161
HGDLRNFIRN
1171

ETHNPTVKDL
1181
IGFGLQVAKG
1191
MKYLASKKFV
1201
HRDLAARNCM
1211
LDEKFTVKVA
1221

DFGLAREYYS
1236
TGAKLPVKWM
1250
ALESLQTQKF
1260
TTKSDVWSFG
1270
VLLWELMTRG
1280

APPYPDVNTF
1290
DITVYLLQGR
1300
RLLQPEYCPD
1310
PLYEVMLKCW
1320
HPKAEMRPSF
1330

SELVSRISAI
1340
FSTFI
Residue
Distance (Å)
ILE1084
3.484
VAL1092
3.234
ALA1108
3.522
LYS1110
3.070
GLU1127
3.383
GLY1128
3.980
MET1131
3.403
PHE1134
3.757
VAL1139
3.601
LEU1140
3.669
VAL1155
4.680
LEU1157
3.775
PRO1158
3.432
TYR1159
3.333
Residue
Distance (Å)
MET1160
3.249
LYS1161
3.891
HIS1162
4.617
GLY1163
3.741
ASP1164
4.773
LEU1195
3.124
PHE1200
3.790
HIS1202
3.799
MET1211
3.470
VAL1220
3.119
ALA1221
3.422
ASP1222
2.765
PHE1223
3.289
GLY1224
4.408
PDB ID: 3LQ8      Structure of the kinase domain of c-Met bound to XL880 (GSK1363089)
Method X-ray diffraction Resolution 2.02 Å Mutation No [2]
PDB Sequence
IDLSALNPEL
1062
VQAVQHVVIG
1072
PSSLIVHFNE
1082
VIGRGHFGCV
1092
YHGTLLDNDG
1102

KKIHCAVKSL
1112
NRIGEVSQFL
1125
TEGIIMKDFS
1135
HPNVLSLLGI
1145
CLSPLVVLPY
1159

MKHGDLRNFI
1169
RNETHNPTVK
1179
DLIGFGLQVA
1189
KGMKYLASKK
1199
FVHRDLAARN
1209

CMLDEKFTVK
1219
VADFGLARDD
1231
KEYYSAKLPV
1247
KWMALESLQT
1257
QKFTTKSDVW
1267

SFGVLLWELM
1277
TRGAPPYPDV
1287
NTFDITVYLL
1297
QGRRLLQPEY
1307
CPDPLYEVML
1317

KCWHPKAEMR
1327
PSFSELVSRI
1337
SAIFSTFI
Residue
Distance (Å)
ILE1084
3.201
VAL1092
3.124
ALA1108
3.357
LYS1110
2.894
GLU1127
3.136
GLY1128
3.858
MET1131
3.418
PHE1134
3.509
VAL1139
3.745
LEU1140
3.547
LEU1157
3.499
PRO1158
3.147
TYR1159
3.284
MET1160
3.051
Residue
Distance (Å)
LYS1161
3.357
HIS1162
3.964
GLY1163
3.689
ASN1171
4.636
LEU1195
3.044
PHE1200
3.877
HIS1202
3.585
MET1211
3.402
VAL1220
3.499
ALA1221
3.589
ASP1222
3.123
PHE1223
3.275
GLY1224
4.631
References  Top
REF 1 Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors. ACS Med Chem Lett. 2019 Aug 2;10(9):1322-1327.
REF 2 Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009 Oct 15;69(20):8009-16.

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