 |
PDBsum entry 3o5x
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase
|
|
|
Title:
|
|
Crystal structure of the oncogenic tyrosine phosphatase shp2 complexed with a salicylic acid-based small molecule inhibitor
|
|
Structure:
|
|
Tyrosine-protein phosphatase non-receptor type 11. Chain: a. Fragment: unp residues 262-532, catalytic domain. Synonym: protein-tyrosine phosphatase 2c, ptp-2c, protein-tyrosine phosphatase 1d, ptp-1d, sh-ptp3, sh-ptp2, shp-2, shp2. Ec: 3.1.3.48
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606
|
|
Resolution:
|
|
|
2.00Å
|
R-factor:
|
0.196
|
R-free:
|
0.238
|
|
|
Authors:
|
|
Z.-Y.Zhang,X.Zhang,Y.He,S.Liu,Z.Yu,Z.Jiang,Z.Yang,Y.Dong, S.C.Nabinger,L.Wu,A.M.Gunawan,L.Wang,R.J.Chan
|
|
Key ref:
|
|
X.Zhang
et al.
(2010).
Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
J Med Chem,
53,
2482-2493.
PubMed id:
|
|
|
Date:
|
|
|
28-Jul-10
|
Release date:
|
11-Aug-10
|
|
|
Supersedes:
|
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
Q06124
(PTN11_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
593 a.a.
255 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.3.1.3.48
- protein-tyrosine-phosphatase.
|
|
|
|
|
|
|
Reaction:
|
|
O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate
|
|
|
|
|
|
O-phospho-L-tyrosyl-[protein]
|
+
|
H2O
|
=
|
L-tyrosyl-[protein]
|
+
|
phosphate
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
|
J Med Chem
53:2482-2493
(2010)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
|
|
X.Zhang,
Y.He,
S.Liu,
Z.Yu,
Z.X.Jiang,
Z.Yang,
Y.Dong,
S.C.Nabinger,
L.Wu,
A.M.Gunawan,
L.Wang,
R.J.Chan,
Z.Y.Zhang.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays
a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2
mutations are associated with Noonan syndrome, various kinds of leukemias, and
solid tumors. Thus, there is considerable interest in SHP2 as a potential target
for anticancer and antileukemia therapy. We report a salicylic acid based
combinatorial library approach aimed at binding both active site and unique
nearby subpockets for enhanced affinity and selectivity. Screening of the
library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with
highly efficacious cellular activity. Compound 9 blocks growth factor stimulated
ERK1/2 activation and hematopoietic progenitor proliferation, providing
supporting evidence that chemical inhibition of SHP2 may be therapeutically
useful for anticancer and antileukemia treatment. X-ray crystallographic
analysis of the structure of SHP2 in complex with 9 reveals molecular
determinants that can be exploited for the acquisition of more potent and
selective SHP2 inhibitors.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
J.Hu,
J.Wu,
C.Li,
L.Zhu,
W.Y.Zhang,
G.Kong,
Z.Lu,
and
C.J.Yang
(2011).
A G-quadruplex aptamer inhibits the phosphatase activity of oncogenic protein Shp2 in vitro.
|
| |
Chembiochem,
12,
424-430.
|
|
|
|
|
|
|
S.Liu,
Z.Yu,
X.Yu,
S.X.Huang,
Y.Luo,
L.Wu,
W.Shen,
Z.Yang,
L.Wang,
A.M.Gunawan,
R.J.Chan,
B.Shen,
and
Z.Y.Zhang
(2011).
SHP2 is a target of the immunosuppressant tautomycetin.
|
| |
Chem Biol,
18,
101-110.
|
|
|
|
|
|
|
V.V.Vintonyak,
H.Waldmann,
and
D.Rauh
(2011).
Using small molecules to target protein phosphatases.
|
| |
Bioorg Med Chem,
19,
2145-2155.
|
|
|
|
|
|
|
R.He,
Z.Yu,
Y.He,
L.F.Zeng,
J.Xu,
L.Wu,
A.M.Gunawan,
L.Wang,
Z.X.Jiang,
and
Z.Y.Zhang
(2010).
Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor.
|
| |
ChemMedChem,
5,
2051-2056.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
|
|
Links
