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PDBsum entry 1c83
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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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2-(Oxalylamino)-Benzoic acid is a general, Competitive inhibitor of protein-Tyrosine phosphatases.
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Authors
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H.S.Andersen,
L.F.Iversen,
C.B.Jeppesen,
S.Branner,
K.Norris,
H.B.Rasmussen,
K.B.Møller,
N.P.Møller.
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Ref.
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J Biol Chem, 2000,
275,
7101-7108.
[DOI no: ]
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PubMed id
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Abstract
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Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of
signal transduction processes. Members of this class of enzymes are considered
attractive therapeutic targets in several disease states, e.g. diabetes, cancer,
and inflammation. However, most reported PTP inhibitors have been
phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors
that covalently modify the enzymes. We therefore embarked on identifying a
general, reversible, competitive PTP inhibitor that could be used as a common
scaffold for lead optimization for specific PTPs. We here report the
identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive
inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and
related non-phosphate low molecular weight derivatives reveals that the binding
mode of these molecules to a large extent mimics that of the natural substrate
including hydrogen bonding to the PTP signature motif. In addition, binding of
OBA to the active site of PTP1B creates a unique arrangement involving Asp(181),
Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the
biological function of specific PTPs and they may eventually be developed into
selective drug candidates. The unique enzyme kinetic features and the low
molecular weight of OBA makes it an ideal starting point for further
optimization.
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Figure 1.
Fig. 1. Structures of OBA and derivatives. 1, OBA; 2,
3-(oxalylamino)-naphthalene-2-carboxylic acid; 3,
6-(oxalylamino)-1H-indole-5-carboxylic acid; 4,
6-(oxalylamino)-1H-indole-7-carboxylic acid; 5,
5-iodo-2-(oxalylamino)-benzoic acid.
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Figure 6.
Fig. 6. o-Carboxy group interactions. A, identical
protein atoms in the Tyr(P)·C215S PTP1B complex and the
compound 1·PTP1B complex are superimposed. The Tyr(P) is
in orange, the Tyr(P)/C215S PTP1B protein is in red, compound 1
is in white, and the PTP1B protein interacting with compound 1
is in yellow. B, the hydrogen bonding network around the
o-carboxy group of compound 1; atoms are colored according to
atom type (carbon in white, oxygen in red, nitrogen in blue, and
iodine in green). Hydrogen bonding lengths are given in Å.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2000,
275,
7101-7108)
copyright 2000.
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