Molecule Information

General Information of the Molecule (ID: Mol00147)
Name
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) ,Homo sapiens
Synonyms
Protein-tyrosine phosphatase 1D; PTP-1D; Protein-tyrosine phosphatase 2C; PTP-2C; SH-PTP2; SHP-2; Shp2; SH-PTP3; PTP2C; SHPTP2
    Click to Show/Hide
Molecule Type
Protein
Gene Name
PTPN11
Gene ID
5781
Location
chr12:112418351-112509918[+]
Sequence
MTSRRWFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTG
DYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGK
EAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYD
VGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAAEIESRVRELSKLAETT
DKVKQGFWEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEP
VSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEV
ERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQGNTERTVWQYHF
RTWPDHGVPSDPGGVLDFLEEVHHKQESIMDAGPVVVHCSAGIGRTGTFIVIDILIDIIR
EKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMAVQHYIETLQRRIEEEQKSKRKGH
EYTNIKYSLADQTSGDQSPLPPCTPTPPCAEMREDSARVYENVGLMQQQKSFR
    Click to Show/Hide
3D-structure
PDB ID
8U7W
Classification
Hydrolase/inhibitor
Method
X-ray diffraction
Resolution
2.05  Å
Function
Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Positively regulates MAPK signal transduction pathway. Dephosphorylates GAB1, ARHGAP35 and EGFR. Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity. Dephosphorylates CDC73. Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification.
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Uniprot ID
PTN11_HUMAN
Ensembl ID
ENSG00000179295
HGNC ID
HGNC:9644
        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
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Preclinical Drug(s)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cryptotanshinone
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: Juvenile myelomonocytic leukaemia [ICD-11: 2A42.0] [1]
Sensitive Disease Juvenile myelomonocytic leukaemia [ICD-11: 2A42.0]
 Disease Info 
Sensitive Drug Cryptotanshinone
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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70
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80
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100
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110
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120
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130
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150
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160
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D
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G
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170
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180
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190
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200
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210
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220
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A
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230
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240
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250
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E
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260
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270
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280
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290
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300
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P
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310
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E
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N
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320
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330
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340
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350
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370
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380
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390
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410
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420
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430
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440
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460
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470
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480
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490
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500
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510
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520
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H
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I
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E
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T
L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter 96 aqueous one solution cell proliferation assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of Cryptotanshinone by unusual activation of pro-survival pathway
II-B08
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: Hematologic Cancer [ICD-11: MG24.Y] [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug II-B08
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
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S
G
M
M
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T
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10
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40
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60
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Y
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Y
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D
L
L
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Y
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G
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E
70
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80
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M
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90
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100
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Y
Y
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P
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L
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N
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C
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P
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T
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S
110
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E
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G
120
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K
K
E
E
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E
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E
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130
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G
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140
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150
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S
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V
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R
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T
G
G
D
D
D
D
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K
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G
E
E
160
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S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
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T
H
H
170
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V
V
M
M
I
I
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R
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C
Q
Q
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E
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Y
Y
180
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D
D
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V
G
G
G
G
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G
E
E
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R
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F
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D
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S
190
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L
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D
L
L
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200
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N
N
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P
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M
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E
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T
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L
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G
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T
V
V
210
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L
L
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L
L
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K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
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R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
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V
V
R
R
E
E
L
L
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S
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K
L
L
A
A
E
E
T
T
240
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T
T
D
D
K
K
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V
K
K
Q
Q
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G
F
F
W
W
E
E
250
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E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
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K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
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R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
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K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
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V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
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P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
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I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
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N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
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T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
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D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
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S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
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V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
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Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
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E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
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		 Western blot analysis
Experiment for
Drug Resistance		 3H-thymidine incorporation assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of II-B08 by unusual activation of pro-survival pathway
SHP099
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: Acute myeloid leukemia [ICD-11: 2A60.0] [3]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug SHP099
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Mechanism Description The SHP2 variant carrying the potent activating mutation E76K exhibits an open-state structure, which induces drastic domain reorganization to expose the active site and eliminate the binding pocket for the allosteric inhibitor SHP099.
Investigative Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
PD98059
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: Acute lymphocytic leukemia [ICD-11: 2B33.0] [4]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Sensitive Drug PD98059
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of PD98059 by unusual activation of pro-survival pathway
U0126
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [4]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Sensitive Drug U0126
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of U0126 by unusual activation of pro-survival pathway
References
Ref 1 Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11)J Med Chem. 2013 Sep 26;56(18):7212-21. doi: 10.1021/jm400474r. Epub 2013 Sep 4.
Ref 2 Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)J Med Chem. 2010 Mar 25;53(6):2482-93. doi: 10.1021/jm901645u.
Ref 3 Selective inhibition of leukemia-associated SHP2(E69K) mutant by the allosteric SHP2 inhibitor SHP099Leukemia. 2018 May;32(5):1246-1249. doi: 10.1038/s41375-018-0020-5. Epub 2018 Jan 30.
Ref 4 Shp2E76K mutant confers cytokine-independent survival of TF-1 myeloid cells by up-regulating Bcl-XLJ Biol Chem. 2007 Dec 14;282(50):36463-73. doi: 10.1074/jbc.M705789200. Epub 2007 Oct 17.

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