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PDBsum entry 1q6j
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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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The structure of phosphotyrosine phosphatase 1b in complex with compound 2
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Structure:
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Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: catalytic domain. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1 or ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.20Å
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R-factor:
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0.215
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R-free:
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0.245
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Authors:
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G.Scapin,S.B.Patel,J.W.Becker,Q.Wang,C.Desponts,D.Waddleton,K.Skorey, W.Cromlish,C.Bayly,M.Therien,J.Y.Gauthier,C.S.Li,C.K.Lau, C.Ramachandran,B.P.Kennedy,E.Asante-Appiah
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Key ref:
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G.Scapin
et al.
(2003).
The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.
Biochemistry,
42,
11451-11459.
PubMed id:
DOI:
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Date:
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13-Aug-03
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Release date:
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30-Sep-03
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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.
289 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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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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Biochemistry
42:11451-11459
(2003)
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PubMed id:
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The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.
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G.Scapin,
S.B.Patel,
J.W.Becker,
Q.Wang,
C.Desponts,
D.Waddleton,
K.Skorey,
W.Cromlish,
C.Bayly,
M.Therien,
J.Y.Gauthier,
C.S.Li,
C.K.Lau,
C.Ramachandran,
B.P.Kennedy,
E.Asante-Appiah.
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ABSTRACT
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Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of
the insulin signaling pathway and represents an attractive target for the design
of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the
structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by
targeting a secondary aryl phosphate-binding site as well as the catalytic site.
We report here the crystal structures of PTP1B in complex with first and second
generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds
bind in a previously unexploited binding pocket near the primary binding site,
the second generation compounds also reach into the secondary binding site, and
exhibit moderate selectivity for PTP1B over the closely related T-cell
phosphatase. The molecular basis for the selectivity has been confirmed by
single point mutation at position 52, where the two phosphatases differ by a
phenylalanine-to-tyrosine switch. These compounds present a novel platform for
the development of potent and selective 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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C.Tuzmen,
and
B.Erman
(2011).
Identification of ligand binding sites of proteins using the gaussian network model.
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PLoS One,
6,
e16474.
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J.P.Yesudas,
F.B.Sayyed,
and
C.H.Suresh
(2011).
Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT.
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J Mol Model,
17,
401-413.
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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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G.W.Han,
C.Bakolitsa,
M.D.Miller,
A.Kumar,
D.Carlton,
R.J.Najmanovich,
P.Abdubek,
T.Astakhova,
H.L.Axelrod,
C.Chen,
H.J.Chiu,
T.Clayton,
D.Das,
M.C.Deller,
L.Duan,
D.Ernst,
J.Feuerhelm,
J.C.Grant,
A.Grzechnik,
L.Jaroszewski,
K.K.Jin,
H.A.Johnson,
H.E.Klock,
M.W.Knuth,
P.Kozbial,
S.S.Krishna,
D.Marciano,
D.McMullan,
A.T.Morse,
E.Nigoghossian,
L.Okach,
R.Reyes,
C.L.Rife,
N.Sefcovic,
H.J.Tien,
C.B.Trame,
H.van den Bedem,
D.Weekes,
Q.Xu,
K.O.Hodgson,
J.Wooley,
M.A.Elsliger,
A.M.Deacon,
A.Godzik,
S.A.Lesley,
and
I.A.Wilson
(2010).
Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
66,
1218-1225.
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PDB codes:
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R.Berrino,
S.Cacchi,
G.Fabrizi,
A.Goggiamani,
and
P.Stabile
(2010).
Arenediazonium tetrafluoroborates in palladium-catalyzed C-P bond-forming reactions. Synthesis of arylphosphonates, -phosphine oxides, and -phosphines.
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Org Biomol Chem,
8,
4518-4520.
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R.Maccari,
R.Ottanà,
R.Ciurleo,
P.Paoli,
G.Manao,
G.Camici,
C.Laggner,
and
T.Langer
(2009).
Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase.
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ChemMedChem,
4,
957-962.
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S.B.Patel,
P.M.Cameron,
S.J.O'Keefe,
B.Frantz-Wattley,
J.Thompson,
E.A.O'Neill,
T.Tennis,
L.Liu,
J.W.Becker,
and
G.Scapin
(2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
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Acta Crystallogr D Biol Crystallogr,
65,
777-785.
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PDB codes:
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K.Bharatham,
N.Bharatham,
and
K.W.Lee
(2007).
Pharmacophore modeling for protein tyrosine phosphatase 1B inhibitors.
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Arch Pharm Res,
30,
533-542.
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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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E.Asante-Appiah,
S.Patel,
C.Desponts,
J.M.Taylor,
C.Lau,
C.Dufresne,
M.Therien,
R.Friesen,
J.W.Becker,
Y.Leblanc,
B.P.Kennedy,
and
G.Scapin
(2006).
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
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J Biol Chem,
281,
8010-8015.
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PDB codes:
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J.Montalibet,
K.Skorey,
D.McKay,
G.Scapin,
E.Asante-Appiah,
and
B.P.Kennedy
(2006).
Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding.
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J Biol Chem,
281,
5258-5266.
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PDB code:
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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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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
