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PDBsum entry 1c87
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Biol Chem, 2000,
275,
10300-10307.
[DOI no: ]
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PubMed id
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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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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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