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PDBsum entry 2qbr
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Contents |
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* Residue conservation analysis
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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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J Med Chem
50:4681-4698
(2007)
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PubMed id:
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Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.
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D.P.Wilson,
Z.K.Wan,
W.X.Xu,
S.J.Kirincich,
B.C.Follows,
D.Joseph-McCarthy,
K.Foreman,
A.Moretto,
J.Wu,
M.Zhu,
E.Binnun,
Y.L.Zhang,
M.Tam,
D.V.Erbe,
J.Tobin,
X.Xu,
L.Leung,
A.Shilling,
S.Y.Tam,
T.S.Mansour,
J.Lee.
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ABSTRACT
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Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin
and leptin receptor pathways and thus an attractive therapeutic target for
diabetes and obesity. Starting with a high micromolar lead compound,
structure-based optimization of novel PTP1B inhibitors by extension of the
molecule from the enzyme active site into the second phosphotyrosine binding
site is described. Medicinal chemistry, guided by X-ray complex structure and
molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient
manner. Compounds from this chemical series were found to be actively
transported into hepatocytes. This active uptake into target tissues could be
one of the possible avenues to overcome the poor membrane permeability of PTP1B
inhibitors.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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P.Stegmaier,
M.Krull,
N.Voss,
A.E.Kel,
and
E.Wingender
(2010).
Molecular mechanistic associations of human diseases.
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BMC Syst Biol,
4,
124.
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Z.Liu,
Q.Chai,
Y.Y.Li,
Q.Shen,
L.P.Ma,
L.N.Zhang,
X.Wang,
L.Sheng,
J.Y.Li,
J.Li,
and
J.K.Shen
(2010).
Discovery of novel PTP1B inhibitors with antihyperglycemic activity.
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Acta Pharmacol Sin,
31,
1005-1012.
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C.O.Kappe,
and
D.Dallinger
(2009).
Controlled microwave heating in modern organic synthesis: highlights from the 2004-2008 literature.
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Mol Divers,
13,
71.
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D.Vidović,
and
S.C.Schürer
(2009).
Knowledge-based characterization of similarity relationships in the human protein-tyrosine phosphatase family for rational inhibitor design.
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J Med Chem,
52,
6649-6659.
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J.F.Wang,
K.Gong,
D.Q.Wei,
Y.X.Li,
and
K.C.Chou
(2009).
Molecular dynamics studies on the interactions of PTP1B with inhibitors: from the first phosphate-binding site to the second one.
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Protein Eng Des Sel,
22,
349-355.
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M.L.Mohler,
Y.He,
Z.Wu,
D.J.Hwang,
and
D.D.Miller
(2009).
Recent and emerging anti-diabetes targets.
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Med Res Rev,
29,
125-195.
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P.I.Tsai,
H.H.Kao,
C.Grabbe,
Y.T.Lee,
A.Ghose,
T.T.Lai,
K.P.Peng,
D.Van Vactor,
R.H.Palmer,
R.H.Chen,
S.R.Yeh,
and
C.T.Chien
(2008).
Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth.
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Neural Develop,
3,
26.
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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.
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Links
