Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T99057 | Target Info | |||
| Target Name | HUMAN 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 | ||||
| Gene Name | MAP2K1 | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | L-betagamma-meATP | Ligand Info | |||
| Canonical SMILES | C1=NC(=C2C(=N1)N(C=N2)C3C(C(C(O3)COP(=O)(O)OP(=O)(CP(=O)(O)O)O)O)O)N | ||||
| InChI | 1S/C11H18N5O12P3/c12-9-6-10(14-2-13-9)16(3-15-6)11-8(18)7(17)5(27-11)1-26-31(24,25)28-30(22,23)4-29(19,20)21/h2-3,5,7-8,11,17-18H,1,4H2,(H,22,23)(H,24,25)(H2,12,13,14)(H2,19,20,21)/t5-,7-,8-,11-/m1/s1 | ||||
| InChIKey | UFZTZBNSLXELAL-IOSLPCCCSA-N | ||||
| PubChem Compound ID | 91532 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 6U2G BRAF-MEK complex with AMP-PCP bound to BRAF | ||||||
| Method | X-ray diffraction | Resolution | 2.89 Å | Mutation | No | [1] |
| PDB Sequence |
DEQQRKRLEA
52 FLTQKQKVGE62 LKDDDFEKIS72 ELGAGNGGVV82 FKVSHKPSGL92 VMARKLIHLE 102 IKPAIRNQII112 RELQVLHECN122 SPYIVGFYGA132 FYSDGEISIC142 MEHMDGGSLD 152 QVLKKAGRIP162 EQILGKVSIA172 VIKGLTYLRE182 KHKIMHRDVK192 PSNILVNSRG 202 EIKLCDFGVS212 GQLIDSMANS222 FVGTRSYMSP232 ERLQGTHYSV242 QSDIWSMGLS 252 LVEMAVGRYP262 IPPPDAKELE272 LMPMAIFELL314 DYIVNEPPPK324 LPSGVFSLEF 334 QDFVNKCLIK344 NPAERADLKQ354 LMVHAFIKRS364 DAEEVDFAGW374 LCSTIGLNQ |
|||||
|
|
GLU102
3.390
LEU74
3.616
GLY75
3.881
ALA76
3.728
GLY77
3.162
ASN78
2.615
GLY79
4.843
GLY80
4.088
VAL81
4.861
VAL82
3.427
ALA95
3.690
LYS97
2.967
VAL127
3.896
|
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| PDB ID: 4MNE Crystal structure of the BRAF:MEK1 complex | ||||||
| Method | X-ray diffraction | Resolution | 2.85 Å | Mutation | No | [2] |
| PDB Sequence |
LKDDDFEKIS
72 ELGAGNGGVV82 FKVSHKPSGL92 VMARKLIHLE102 IKPAIRNQII112 RELQVLHECN 122 SPYIVGFYGA132 FYSDGEISIC142 MEHMDGGSLD152 QVLKKAGRIP162 EQILGKVSIA 172 VIKGLTYLRE182 KHKIMHRDVK192 PSNILVNSRG202 EIKLCDFGVS212 GQLIDSMANS 222 FVGTRSYMSP232 ERLQGTHYSV242 QSDIWSMGLS252 LVEMAVGRYP262 IPPPDAKELE 272 LMPPMAIFEL313 LDYIVNEPPP323 KLPSGVFSLE333 FQDFVNKCLI343 KNPAERADLK 353 QLMVHAFIKR363 SDAEEVDFAG373 WLCSTI
|
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|
|
LEU74
3.706
GLY75
3.641
ALA76
3.459
GLY77
3.380
ASN78
2.972
GLY80
3.678
VAL81
4.434
VAL82
3.618
ALA95
3.583
LYS97
2.735
VAL127
4.292
MET143
3.384
GLU144
3.172
|
|||||
| PDB ID: 4ANB Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs. | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [3] |
| PDB Sequence |
MALGELKDDD
67 FEKISELGAG77 NGGVVFKVSH87 KPSGLVMARK97 LIHLEIKPAI107 RNQIIRELQV 117 LHECNSPYIV127 GFYGAFYSDG137 EISICMEHMD147 GGSLDQVLKK157 AGRIPEQILG 167 KVSIAVIKGL177 TYLREKHKIM187 HRDVKPSNIL197 VNSRGEIKLC207 DFGVSGQLID 217 EMANEFVGTR227 SYMSPERLQG237 THYSVQSDIW247 SMGLSLVEMA257 VGRYPRPPMA 309 IFELLDYIVN319 EPPPKLPSAV329 FSLEFQDFVN339 KCLIKNPAER349 ADLKQLMVHA 359 FIKRSDAEEV369 DFAGWLCSTI379 GL
|
|||||
|
|
LEU74
3.369
GLY75
3.586
ALA76
3.867
GLY77
3.059
ASN78
2.399
GLY79
4.675
GLY80
3.500
VAL81
4.846
VAL82
3.461
ALA95
3.273
LYS97
3.014
VAL127
4.325
MET143
3.607
GLU144
3.018
|
|||||
| PDB ID: 4AN2 Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs. | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [3] |
| PDB Sequence |
MALGELKDDD
67 FEKISELGAG77 NGGVVFKVSH87 KPSGLVMARK97 LIHLEIKPAI107 RNQIIRELQV 117 LHECNSPYIV127 GFYGAFYSDG137 EISICMEHMD147 GGSLDQVLKK157 AGRIPEQILG 167 KVSIAVIKGL177 TYLREKHKIM187 HRDVKPSNIL197 VNSRGEIKLC207 DFGVSGQLID 217 EMANEFVGTR227 SYMSPERLQG237 THYSVQSDIW247 SMGLSLVEMA257 VGRYPRPPMA 309 IFELLDYIVN319 EPPPKLPSAV329 FSLEFQDFVN339 KCLIKNPAER349 ADLKQLMVHA 359 FIKRSDAEEV369 DFAGWLCSTI379 GL
|
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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 .ACP or .ACP2 or .ACP3 or :3ACP;style chemicals stick;color identity;select .A:74 or .A:75 or .A:76 or .A:77 or .A:78 or .A:79 or .A:80 or .A:82 or .A:95 or .A:97 or .A:127 or .A:143 or .A:144 or .A:145 or .A:146 or .A:149 or .A:150 or .A:153 or .A:190 or .A:192 or .A:194 or .A:195 or .A:197 or .A:207 or .A:208 or .A:226; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU74
3.513
GLY75
3.577
ALA76
3.966
GLY77
3.241
ASN78
2.710
GLY79
4.753
GLY80
3.429
VAL82
3.629
ALA95
3.322
LYS97
3.015
VAL127
4.274
MET143
3.687
GLU144
3.036
|
|||||
| PDB ID: 4AN9 Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs. | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [3] |
| PDB Sequence |
MALGELKDDD
67 FEKISELGAG77 NGGVVFKVSH87 KPSGLVMARK97 LIHLEIKPAI107 RNQIIRELQV 117 LHECNSPYIV127 GFYGAFYSDG137 EISICMEHMD147 GGSLDQVLKK157 AGRIPEQILG 167 KVSIAVIKGL177 TYLREKHKIM187 HRDVKPSNIL197 VNSRGEIKLC207 DFGVSGQLID 217 EMANEVGTRS228 YMSPERLQGT238 HYSVQSDIWS248 MGLSLVEMAV258 GRYPRPPMAI 310 FELLDYIVNE320 PPPKLPSAVF330 SLEFQDFVNK340 CLIKNPAERA350 DLKQLMVHAF 360 IKRSDAEEVD370 FAGWLCSTIG380 L
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ACP or .ACP2 or .ACP3 or :3ACP;style chemicals stick;color identity;select .A:74 or .A:75 or .A:76 or .A:77 or .A:78 or .A:79 or .A:80 or .A:82 or .A:95 or .A:97 or .A:127 or .A:143 or .A:144 or .A:145 or .A:146 or .A:149 or .A:150 or .A:153 or .A:190 or .A:192 or .A:194 or .A:195 or .A:197 or .A:207 or .A:208; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU74
3.637
GLY75
3.614
ALA76
3.664
GLY77
3.224
ASN78
2.896
GLY79
4.047
GLY80
4.916
VAL82
3.855
ALA95
3.515
LYS97
3.358
VAL127
4.061
MET143
3.285
GLU144
2.956
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization. Nat Struct Mol Biol. 2020 Feb;27(2):134-141. | ||||
| REF 2 | Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. Cancer Cell. 2014 Sep 8;26(3):402-413. | ||||
| REF 3 | Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett. 2012 Apr 9;3(5):416-21. | ||||
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