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PDBsum entry 1c88
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Crystal structure of protein tyrosine phosphatase 1b complexed with 2- (oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid
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Structure:
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Protein (protein-tyrosine phosphatase 1b). Chain: a. Synonym: ptp1b. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.80Å
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R-factor:
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0.200
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R-free:
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0.228
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Authors:
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L.F.Iversen,H.S.Andersen,S.B.Mortensen,N.P.Moller
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Key ref:
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L.F.Iversen
et al.
(2000).
Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.
J Biol Chem,
275,
10300-10307.
PubMed id:
DOI:
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Date:
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16-Apr-00
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Release date:
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03-May-00
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PROCHECK
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Headers
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References
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P18031
(PTN1_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 1 from Homo sapiens
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Seq:
Struc:
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435 a.a.
297 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 2 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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J Biol Chem
275:10300-10307
(2000)
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PubMed id:
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Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.
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L.F.Iversen,
H.S.Andersen,
S.Branner,
S.B.Mortensen,
G.H.Peters,
K.Norris,
O.H.Olsen,
C.B.Jeppesen,
B.F.Lundt,
W.Ripka,
K.B.Møller,
N.P.Møller.
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ABSTRACT
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Several protein-tyrosine phosphatases (PTPs) have been proposed to act as
negative regulators of insulin signaling. Recent studies have shown increased
insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus
pointing to this enzyme as a potential drug target in diabetes. Structure-based
design, guided by PTP mutants and x-ray protein crystallography, was used to
optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor
(2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This
was achieved by addressing residue 48 as a selectivity determining residue. By
introducing a basic nitrogen in the core structure of the inhibitor, a salt
bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes
repulsion in other PTPs containing an asparagine in the equivalent position
resulting in a remarkable selectivity for PTP1B. Importantly, this was
accomplished while retaining the molecular weight of the inhibitor below 300
g/mol.
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Selected figure(s)
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Figure 1.
Fig. 1. Chemical structures of OBA-1 and its derivatives.
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Figure 4.
Fig. 4. Schematic representation of compound 5 in the
active site pocket of PTP1B. Distances are in Å for
noncovalent interactions between PTP1B and compound 5. Van der
Waals interactions are illustrated by arcs. Nomenclature used
for the different groups of compound 5.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2000,
275,
10300-10307)
copyright 2000.
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Figures were
selected
by an automated process.
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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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Y.Huang,
and
A.Dömling
(2011).
The Gewald multicomponent reaction.
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Mol Divers,
15,
3.
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B.Townshend,
I.Aubry,
R.C.Marcellus,
K.Gehring,
and
M.L.Tremblay
(2010).
An RNA aptamer that selectively inhibits the enzymatic activity of protein tyrosine phosphatase 1B in vitro.
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Chembiochem,
11,
1583-1593.
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C.Abad-Zapatero,
O.Perišić,
J.Wass,
A.P.Bento,
J.Overington,
B.Al-Lazikani,
and
M.E.Johnson
(2010).
Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation.
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Drug Discov Today,
15,
804-811.
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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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K.Hellmuth,
S.Grosskopf,
C.T.Lum,
M.Würtele,
N.Röder,
J.P.von Kries,
M.Rosario,
J.Rademann,
and
W.Birchmeier
(2008).
Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking.
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Proc Natl Acad Sci U S A,
105,
7275-7280.
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A.C.Bishop,
X.Y.Zhang,
and
A.M.Lone
(2007).
Generation of inhibitor-sensitive protein tyrosine phosphatases via active-site mutations.
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Methods,
42,
278-288.
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M.Stuible,
L.Zhao,
I.Aubry,
D.Schmidt-Arras,
F.D.Böhmer,
C.J.Li,
and
M.L.Tremblay
(2007).
Cellular inhibition of protein tyrosine phosphatase 1B by uncharged thioxothiazolidinone derivatives.
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Chembiochem,
8,
179-186.
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R.Maccari,
P.Paoli,
R.Ottanà,
M.Jacomelli,
R.Ciurleo,
G.Manao,
T.Steindl,
T.Langer,
M.G.Vigorita,
and
G.Camici
(2007).
5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases.
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Bioorg Med Chem,
15,
5137-5149.
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T.Sun,
Q.Wang,
Z.Yu,
Y.Zhang,
Y.Guo,
K.Chen,
X.Shen,
and
H.Jiang
(2007).
Hyrtiosal, a PTP1B inhibitor from the marine sponge Hyrtios erectus, shows extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFbeta/Smad2 signaling.
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Chembiochem,
8,
187-193.
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A.G.Evdokimov,
M.Pokross,
R.Walter,
M.Mekel,
B.Cox,
C.Li,
R.Bechard,
F.Genbauffe,
R.Andrews,
C.Diven,
B.Howard,
V.Rastogi,
J.Gray,
M.Maier,
and
K.G.Peters
(2006).
Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.
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Acta Crystallogr D Biol Crystallogr,
62,
1435-1445.
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PDB codes:
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D.Tolkatchev,
R.Shaykhutdinov,
P.Xu,
J.Plamondon,
D.C.Watson,
N.M.Young,
and
F.Ni
(2006).
Three-dimensional structure and ligand interactions of the low molecular weight protein tyrosine phosphatase from Campylobacter jejuni.
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Protein Sci,
15,
2381-2394.
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PDB code:
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E.W.Yue,
B.Wayland,
B.Douty,
M.L.Crawley,
E.McLaughlin,
A.Takvorian,
Z.Wasserman,
M.J.Bower,
M.Wei,
Y.Li,
P.J.Ala,
L.Gonneville,
R.Wynn,
T.C.Burn,
P.C.Liu,
and
A.P.Combs
(2006).
Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold.
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Bioorg Med Chem,
14,
5833-5849.
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A.K.Pedersen,
G.H.Peters G,
K.B.Møller,
L.F.Iversen,
and
J.S.Kastrup
(2004).
Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B.
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Acta Crystallogr D Biol Crystallogr,
60,
1527-1534.
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PDB code:
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C.Wiesmann,
K.J.Barr,
J.Kung,
J.Zhu,
D.A.Erlanson,
W.Shen,
B.J.Fahr,
M.Zhong,
L.Taylor,
M.Randal,
R.S.McDowell,
and
S.K.Hansen
(2004).
Allosteric inhibition of protein tyrosine phosphatase 1B.
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Nat Struct Mol Biol,
11,
730-737.
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PDB codes:
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S.D.Taylor,
and
B.Hill
(2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
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Expert Opin Investig Drugs,
13,
199-214.
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T.Honma
(2003).
Recent advances in de novo design strategy for practical lead identification.
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Med Res Rev,
23,
606-632.
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T.M.Frimurer,
G.H.Peters,
L.F.Iversen,
H.S.Andersen,
N.P.Møller,
and
O.H.Olsen
(2003).
Ligand-induced conformational changes: improved predictions of ligand binding conformations and affinities.
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Biophys J,
84,
2273-2281.
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Z.Y.Zhang,
and
S.Y.Lee
(2003).
PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity.
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Expert Opin Investig Drugs,
12,
223-233.
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E.Asante-Appiah,
S.Patel,
C.Dufresne,
P.Roy,
Q.Wang,
V.Patel,
R.W.Friesen,
C.Ramachandran,
J.W.Becker,
Y.Leblanc,
B.P.Kennedy,
and
G.Scapin
(2002).
The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates.
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Biochemistry,
41,
9043-9051.
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PDB code:
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H.Fu,
J.Park,
and
D.Pei
(2002).
Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases.
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Biochemistry,
41,
10700-10709.
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T.Haruyama,
E.Kobatake,
and
M.Aizawa
(2002).
Cellular biosensing system for discovery of protein synthesis inhibitors with an electrochemical phosphate modulator to regulate the acid phosphatase gene expression of Saccharomyces cerevisiae.
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Biosens Bioelectron,
17,
209-215.
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T.O.Johnson,
J.Ermolieff,
and
M.R.Jirousek
(2002).
Protein tyrosine phosphatase 1B inhibitors for diabetes.
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Nat Rev Drug Discov,
1,
696-709.
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Z.Y.Zhang
(2002).
Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development.
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Annu Rev Pharmacol Toxicol,
42,
209-234.
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G.Scapin,
S.Patel,
V.Patel,
B.Kennedy,
and
E.Asante-Appiah
(2001).
The structure of apo protein-tyrosine phosphatase 1B C215S mutant: more than just an S --> O change.
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Protein Sci,
10,
1596-1605.
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PDB code:
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J.N.Andersen,
O.H.Mortensen,
G.H.Peters,
P.G.Drake,
L.F.Iversen,
O.H.Olsen,
P.G.Jansen,
H.S.Andersen,
N.K.Tonks,
and
N.P.Møller
(2001).
Structural and evolutionary relationships among protein tyrosine phosphatase domains.
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Mol Cell Biol,
21,
7117-7136.
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M.Balasubramanyam,
and
V.Mohan
(2001).
Orally active insulin mimics: where do we stand now?
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J Biosci,
26,
383-390.
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Z.Y.Zhang
(2001).
Protein tyrosine phosphatases: prospects for therapeutics.
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Curr Opin Chem Biol,
5,
416-423.
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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.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
