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PDBsum entry 3zm0
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PDB id:
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Hydrolase
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Title:
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Catalytic domain of human shp2
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Structure:
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Tyrosine-protein phosphatase non-receptor type 11. Chain: a. Fragment: catalytic domain, residues 248-527. Synonym: protein-tyrosine phosphatase 1d, ptp-1d, protein-tyrosine phosphatase 2c, ptp-2c, sh-ptp2, shp-2, shp2, sh-ptp3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: scs1 rosetta t1r.
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Resolution:
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1.50Å
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R-factor:
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0.186
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R-free:
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0.213
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Authors:
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K.Bohm,A.Schuetz,Y.Roske,U.Heinemann
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Key ref:
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S.Grosskopf
et al.
(2015).
Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo.
Chemmedchem,
10,
815-826.
PubMed id:
DOI:
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Date:
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04-Feb-13
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Release date:
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23-Apr-14
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PROCHECK
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Headers
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References
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Q06124
(PTN11_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens
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Seq:
Struc:
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593 a.a.
261 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
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Enzyme class:
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E.C.3.1.3.48
- protein-tyrosine-phosphatase.
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Reaction:
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O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate
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O-phospho-L-tyrosyl-[protein]
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+
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H2O
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=
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L-tyrosyl-[protein]
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+
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phosphate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Chemmedchem
10:815-826
(2015)
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PubMed id:
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Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo.
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S.Grosskopf,
C.Eckert,
C.Arkona,
S.Radetzki,
K.Böhm,
U.Heinemann,
G.Wolber,
J.P.von Kries,
W.Birchmeier,
J.Rademann.
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ABSTRACT
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Selective inhibitors of the protein tyrosine phosphatase SHP2 (src homology
region 2 domain phosphatase; PTPN11), an enzyme that is deregulated in
numerous human tumors, were generated through a combination of chemical
synthesis and structure-based rational design. Seventy
pyridazolon-4-ylidenehydrazinyl benzenesulfonates were prepared and evaluated in
enzyme assays. The binding modes of active inhibitors were simulated in silico
using a newly generated crystal structure of SHP2. The most powerful compound,
GS-493
(4-{(2Z)-2-[1,3-bis(4-nitrophenyl)-5-oxo-1,5-dihydro-4H-pyrazol-4-yliden]hydrazino}benzenesulfonic
acid; 25) inhibited SHP2 with an IC50 value of 71±15 nM in the enzyme assay
and was 29- and 45-fold more active toward SHP2 than against related SHP1 and
PTP1B. In cell culture experiments compound 25 was found to block hepatocyte
growth factor (HGF)-stimulated epithelial-mesenchymal transition of human
pancreatic adenocarcinoma (HPAF) cells, as indicated by a decrease in the
minimum neighbor distances of cells. Moreover, 25 inhibited cell colony
formation in the non-small-cell lung cancer cell line LXFA 526L in soft agar.
Finally, 25 was observed to inhibit tumor growth in a murine xenograft model.
Therefore, the novel specific compound 25 strengthens the hypothesis that SHP2
is a relevant protein target for the inhibition of mobility and invasiveness of
cancer cells.
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