 |
PDBsum entry 4rdd
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
4rdd
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase/hydrolase inhibitor
|
|
|
Title:
|
|
Co-crystal structure of shp2 in complex with a cefsulodin derivative
|
|
Structure:
|
|
Tyrosine-protein phosphatase non-receptor type 11. Chain: a. Fragment: shp2 catalytic domain. Synonym: protein-tyrosine phosphatase 1d, ptp-1d, protein-tyrosine phosphatase 2c, ptp-2c, sh-ptp2, shp-2, shp2, sh-ptp3. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn11, ptp2c, shptp2. Expressed in: escherichia coli. Expression_system_taxid: 469008.
|
|
Resolution:
|
|
|
1.60Å
|
R-factor:
|
0.177
|
R-free:
|
0.201
|
|
|
Authors:
|
|
Z.Y.Zhang,Z.H.Yu,R.He,R.Y.Zhang
|
|
Key ref:
|
|
R.He
et al.
(2015).
Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.
Acs Med Chem Lett,
6,
782-786.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
18-Sep-14
|
Release date:
|
01-Jul-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
Q06124
(PTN11_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
593 a.a.
267 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
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Acs Med Chem Lett
6:782-786
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.
|
|
R.He,
Z.H.Yu,
R.Y.Zhang,
L.Wu,
A.M.Gunawan,
B.S.Lane,
J.S.Shim,
L.F.Zeng,
Y.He,
L.Chen,
C.D.Wells,
J.O.Liu,
Z.Y.Zhang.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many
diseases. Unfortunately, despite considerable drug discovery efforts devoted to
PTPs, obtaining selective and cell permeable PTP inhibitors remains highly
challenging. We describe a strategy to explore the existing drug space for
previously unknown PTP inhibitory activities. This led to the discovery of
cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family.
Crystal structure analysis of SHP2 interaction with cefsulodin identified
sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A
structure-guided and SPAA fragment-based focused library approach produced
several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked
SHP2-mediated signaling events and proliferation in several cancer cell lines.
Thus, SPAA may serve as a new platform for developing chemical probes for other
PTPs.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
