Molecule Information

General Information of the Molecule (ID: Mol00509)
Name
MAPK/ERK kinase 1 (MEK1) ,Homo sapiens
Synonyms
MAP kinase kinase 1; MAPKK 1; MKK1; ERK activator kinase 1; MAPK/ERK kinase 1; MEK 1; MEK1; PRKMK1
    Click to Show/Hide
Molecule Type
Protein
Gene Name
MAP2K1
Gene ID
5604
Location
chr15:66386837-66491656[+]
Sequence
MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV
    Click to Show/Hide
3D-structure
PDB ID
6U2G
Classification
Transferase
Method
X-ray diffraction
Resolution
2.89  Å
Function
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.
    Click to Show/Hide
Uniprot ID
MP2K1_HUMAN
Ensembl ID
ENSG00000169032
HGNC ID
HGNC:6840
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Regorafenib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of Regorafenib by unusual activation of pro-survival pathway
Clinical Trial Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
PLX4720
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug PLX4720
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
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M
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A
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H
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P
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H
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E
E
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N
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P
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I
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G
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F
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Y
Y
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G
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S
S
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I
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C
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E
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M
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D
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G
G
G
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S
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L
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D
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K
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A
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G
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R
R
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L
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G
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K
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V
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S
S
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I
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A
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V
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I
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G
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L
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T
Y
Y
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L
L
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K
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I
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M
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D
D
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V
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K
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P
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S
N
N
I
I
L
L
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V
N
N
200
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S
S
R
R
G
G
E
E
I
I
K
K
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L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Discontinued Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
AZD-8330
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug AZD-8330
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of AZD-8330 by unusual activation of pro-survival pathway
Preclinical Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cetuximab/Trametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Sensitive Drug Cetuximab/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI-H508 cells Colon Homo sapiens (Human) CVCL_1564
CCK-81 cells N.A. Homo sapiens (Human) CVCL_2873
GDC0879
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug GDC0879
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of GDC0879 by unusual activation of pro-survival pathway
Investigative Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
MEK inhibitors
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Melanoma [ICD-11: 2C30.0] [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Resistant Drug MEK inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Human melanoma tissue N.A.
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of MEK inhibitors by unusual activation of pro-survival pathway
PD98059
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [1]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug PD98059
 Drug Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the resistance of PD98059 by unusual activation of pro-survival pathway
References
Ref 1 Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancersBiochim Biophys Acta Proteins Proteom. 2019 Jan;1867(1):62-70. doi: 10.1016/j.bbapap.2018.05.004. Epub 2018 May 9.
Ref 2 Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutationsGenome Res. 2017 Apr;27(4):613-625. doi: 10.1101/gr.213546.116. Epub 2017 Feb 8.
Ref 3 Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profilingJ Clin Oncol. 2011 Aug 1;29(22):3085-96. doi: 10.1200/JCO.2010.33.2312. Epub 2011 Mar 7.

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