PDBsum entry 3cby

Protein binding

PDB id: 3cby

Contents

Protein chains

101 a.a. *

98 a.a. *

Ligands

EDO ×2

Waters ×198

* Residue conservation analysis

PDB id:

3cby

Name:

Protein binding

Title:

The dvl2 pdz domain in complex with the n1 inhibitory peptide

Structure:

Dishevelled-2. Chain: a, b. Fragment: pdz domain (unp residues 264-354). Synonym: segment polarity protein dishevelled homolog dvl-2, dsh homolog 2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dvl2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.50Å R-factor: 0.136 R-free: 0.182

Authors:

B.A.Appleton,C.Wiesmann

Key ref:

Y.Zhang et al. (2009). Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nat Chem Biol, 5, 217-219. PubMed id: 19252499 DOI: 10.1038/nchembio.152

Date:

23-Feb-08 Release date: 03-Mar-09

Protein chain

O14641  (DVL2_HUMAN) -  Segment polarity protein dishevelled homolog DVL-2 from Homo sapiens

Seq: 736 a.a.

Struc: 101 a.a.*

Protein chain

O14641  (DVL2_HUMAN) -  Segment polarity protein dishevelled homolog DVL-2 from Homo sapiens

Seq: 736 a.a.

Struc: 98 a.a.*

* PDB and UniProt seqs differ at 28 residue positions (black crosses)

DOI no: 10.1038/nchembio.152

Nat Chem Biol 5:217-219 (2009)

PubMed id: 19252499

Inhibition of Wnt signaling by Dishevelled PDZ peptides.

Y.Zhang, B.A.Appleton, C.Wiesmann, T.Lau, M.Costa, R.N.Hannoush, S.S.Sidhu.

ABSTRACT

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.

Selected figure(s)

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.

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).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2009, 5, 217-219) copyright 2009.