Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T35940 | Target Info | |||
| Target Name | ERK activator kinase 1 (MEK1) | ||||
| Synonyms | PRKMK1; Mitogen-activated protein kinase kinase 1; MKK1; MEK 1; MAPKK 1; MAPK/ERKkinase 1; MAPK/ERK kinase 1; MAP kinase kinase 1; Dual specificity mitogen-activated protein kinase kinase 1 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | MAP2K1 | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | RO-5126766 | Ligand Info | |||
| Canonical SMILES | CC1=C(C(=O)OC2=C1C=CC(=C2)OC3=NC=CC=N3)CC4=C(C(=NC=C4)NS(=O)(=O)NC)F | ||||
| InChI | 1S/C21H18FN5O5S/c1-12-15-5-4-14(31-21-25-7-3-8-26-21)11-17(15)32-20(28)16(12)10-13-6-9-24-19(18(13)22)27-33(29,30)23-2/h3-9,11,23H,10H2,1-2H3,(H,24,27) | ||||
| InChIKey | LMMJFBMMJUMSJS-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 16719221 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7MFD Autoinhibited BRAF:(14-3-3)2:MEK complex with the BRAF RBD resolved | ||||||
| Method | Electron microscopy | Resolution | 3.66 Å | Mutation | No | [1] |
| PDB Sequence |
AFLTQKQKVG
61 ELKDDDFEKI71 SELGAGNGGV81 VFKVSHKPSG91 LVMARKLIHL101 EIKPAIRNQI 111 IRELQVLHEC121 NSPYIVGFYG131 AFYSDGEISI141 CMEHMDGGSL151 DQVLKKAGRI 161 PEQILGKVSI171 AVIKGLTYLR181 EKHKIMHRDV191 KPSNILVNSR201 GEIKLCDFGV 211 SGQLIDSMAN221 SFVGTRSYMS231 PERLQGTHYS241 VQSDIWSMGL251 SLVEMAVGRY 261 PIPPPDPMAI310 FELLDYIVNE320 PPPKLPSGVF330 SLEFQDFVNK340 CLIKNPAERA 350 DLKQLMVHAF360 IKRSDAEEVD370 FAGWLCSTIG380 LNQ
|
|||||
|
|
LYS97
4.012
LEU118
3.306
ILE126
3.859
VAL127
3.308
GLY128
4.705
PHE129
4.111
ILE141
3.502
MET143
3.172
HIS188
4.074
ARG189
2.943
ASP190
3.290
LEU206
4.932
CYS207
3.769
|
|||||
| PDB ID: 7M0Z Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and CH5126766 | ||||||
| Method | X-ray diffraction | Resolution | 3.12 Å | Mutation | Yes | [2] |
| PDB Sequence |
LDEQQRKRLE
51 AFLTQKQKVG61 ELKDDDFEKI71 SELGAGNGGV81 VFKVSHKPSG91 LVMARKLIHL 101 EIKPAIRNQI111 IRELQVLHEC121 NSPYIVGFYG131 AFYSDGEISI141 CMEHMDGGSL 151 DQVLKKAGRI161 PEQILGKVSI171 AVIKGLTYLR181 EKHKIMHRDV191 KPSNILVNSR 201 GEIKLCDFGV211 SGQLIDAMAN221 AFVGTRSYMS231 PERLQGTHYS241 VQSDIWSMGL 251 SLVEMAVGRY261 PIPPPDAKEL271 ELMPMAIFEL313 LDYIVNEPPP323 KLPSGVFSLE 333 FQDFVNKCLI343 KNPAERADLK353 QLMVHAFIKR363 SDAEEVDFAG373 WLCSTIGLNQ 383
|
|||||
|
|
LYS97
4.341
ILE99
4.722
LEU115
3.923
LEU118
3.671
ILE126
4.433
VAL127
3.574
GLY128
4.156
PHE129
3.991
ILE141
3.301
MET143
3.968
HIS188
3.693
ARG189
2.809
ASP190
3.631
|
|||||
| PDB ID: 3WIG Human MEK1 kinase in complex with CH5126766 and MgAMP-PNP | ||||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [3] |
| PDB Sequence |
MELKDDDFEK
71 ISELGAGVVF84 KVSHKPSGLV94 MARKLIHLEI104 KPAIRNQIIR114 ELQVLHECNS 124 PYIVGFYGAF134 YSDGEISICM144 EHMDGGSLDQ154 VLKKAGRIPE164 QILGKVSIAV 174 IKGLTYLREK184 HKIMHRDVKP194 SNILVNSRGE204 IKLCDFGVSG214 QLIDSMANSF 224 VGTRSYMSPE234 RLQGTHYSVQ244 SDIWSMGLSL254 VEMAVGRYPI264 PPPPPMAIFE 312 LLDYIVNEPP322 PKLPSGVFSL332 EFQDFVNKCL342 IKNPAERADL352 KQLMVHAFIK 362 RSDAEEVDFA372 GWLCSTIG
|
|||||
|
|
LYS98
4.204
ILE100
4.421
LEU116
3.815
LEU119
3.331
ILE127
4.351
VAL128
3.126
GLY129
3.673
PHE130
3.838
ILE142
3.045
MET144
3.321
HIS189
3.682
ARG190
2.907
ASP191
3.604
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding. Nat Commun. 2022 Jan 25;13(1):486. | ||||
| REF 2 | Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2107207118. | ||||
| REF 3 | Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell. 2014 May 12;25(5):697-710. | ||||
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