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PDBsum entry 3cbx
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Protein binding
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PDB id
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3cbx
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References listed in PDB file
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Key reference
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Title
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Inhibition of wnt signaling by dishevelled pdz peptides.
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Authors
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Y.Zhang,
B.A.Appleton,
C.Wiesmann,
T.Lau,
M.Costa,
R.N.Hannoush,
S.S.Sidhu.
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Ref.
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Nat Chem Biol, 2009,
5,
217-219.
[DOI no: ]
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PubMed id
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Abstract
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Dishevelled proteins are key regulators of Wnt signaling pathways that have been
implicated in the progression of human cancers. We found that the binding cleft
of the Dishevelled PDZ domain is more flexible than those of canonical PDZ
domains and enables recognition of both C-terminal and internal peptides. These
peptide ligands inhibit Wnt/beta-catenin signaling in cells, showing that
Dishevelled PDZ domains are potential targets for small-molecule cancer
therapeutics.
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Figure 1.
(a) Erbin-PDZ in complex with a C-terminal peptide
(WETWV[COOH], PDB entry 1N7T, deposited as part of a previous
study). (b) Dvl2-PDZ in complex with C-terminal pep-C1
(WKWYGWF[COOH], K[i] = 0.7  0.2
 M).
(c) Dvl2-PDZ in complex with internal peptide pep-N1
(WKDYGWIDGK, K[i] = 1.2 0.3
M).
(d) Dvl2-PDZ in complex with internal peptide pep-N2
(SGNEVWIDGP). (e) Dvl2-PDZ in complex with internal peptide
pep-N3 (EIVLWSDIP, K[i] = 4.6 2.2
M).
In the left panels, the peptides (shown as sticks) are colored
according to their interactions with subsites on the PDZ domains
(green, site C; orange, site 0; magenta, site -1; blue, site -2;
yellow, site -3; tan, other residues). The right panels show
surface representations of the PDZ domains, with subsites
colored as described for the left panels, and peptide ligands
colored according to atom type (tan, carbon; blue, nitrogen;
red, oxygen). The peptide residues are labeled according to the
subsites they occupy on the PDZ domain.
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Figure 2.
(a) Real-time cellular uptake of pen-N3 visualized by
time-lapse microscopy. For a full movie, see Supplementary Movie
1. DIC, differential interference contrast; FITC, fluorescein
isothiocyanate. (b) Pen-N3 inhibits Wnt/TCF-dependent signaling.
Normalized TOPglow reporter activity was measured in
Wnt3a-stimulated HEK293S cells after 18 h of treatment with
pen-N3, compound FJ9 or pen as negative control. (c) Pen-N3
inhibits accumulation of  -catenin
in HEK293S cells treated with Wnt3a. Cells were treated with
Wnt3a (100 ng ml^-1) for 18 h in the presence of the indicated
peptides (10 M),
lysed and processed for western blots. The antibody labels -catenin
(solid arrow) and also a nonspecific band (hollow arrow).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2009,
5,
217-219)
copyright 2009.
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