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PDBsum entry 2cmc
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References listed in PDB file
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Key reference
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Title
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Structural basis for inhibition of protein-Tyrosine phosphatase 1b by isothiazolidinone heterocyclic phosphonate mimetics.
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Authors
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P.J.Ala,
L.Gonneville,
M.C.Hillman,
M.Becker-Pasha,
M.Wei,
B.G.Reid,
R.Klabe,
E.W.Yue,
B.Wayland,
B.Douty,
P.Polam,
Z.Wasserman,
M.Bower,
A.P.Combs,
T.C.Burn,
G.F.Hollis,
R.Wynn.
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Ref.
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J Biol Chem, 2006,
281,
32784-32795.
[DOI no: ]
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PubMed id
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Abstract
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Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds
bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal
that the heterocycle is highly complementary to the catalytic pocket of the
protein. The heterocycle participates in an extensive network of hydrogen bonds
with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the
side chain of Arg(221). When substituted with a phenol, the small inhibitor
induces the closed conformation of the protein and displaces all waters in the
catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors
than unsaturated analogs because the IZD heterocycle and phenyl ring directly
attached to it bind in a nearly orthogonal orientation with respect to each
other, a conformation that is close to the energy minimum of the saturated
IZD-phenyl moiety. These results explain why the heterocycle is a potent
phosphonate mimetic and an ideal starting point for designing small nonpeptidic
inhibitors.
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Figure 2.
FIGURE 2. Crystal structure of PTP1B/1. a, superposition of
the bound conformations of the phosphonate mimetics of compounds
1, 5, and 1G7G. Note the IZD heterocycle of 1 mimics the
interactions of DFMP and CMBA, and it displaces four waters. b,
stereo view of the 2F[o] - F[c] simulated annealed omit map
(contoured at 1  ) and atomic model for
PTP1B/1. The inhibitor was omitted from the model prior to a
cycle of simulated annealing and was not used in the calculation
of phases. c, stereo view of 1 (ball-and-stick) bound in the A
site. Dashed lines indicate 10 potential hydrogen bonds between
the inhibitor and residues in the active site.
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Figure 6.
FIGURE 6. Bound conformations of saturated and unsaturated
IZD-phenyl moieties. a, the relative angle between the
unsaturated IZD and phenyl rings of 1 is  70-75°. b,
superposition of the unsaturated IZD 1 (stick bonds) and the
saturated (S)-IZD-phenyl moiety of 2 (ball-and-stick). Note the
phenyl ring and heteroatoms of IZD bind in the same position
whether or not the heterocycle is reduced.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
32784-32795)
copyright 2006.
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