Identification of Tripeptides Recognized by the PDZ Domain of Dishevelled

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2009 Jan 23

PMID 19157887

Citations 12

Authors

Ho-Jin Lee

Nick X Wang

Youming Shao

Jie J Zheng

Affiliations

Soon will be listed here.

Abstract

The development of inhibitors of Dishevelled (Dvl) PDZ protein-protein interactions attracts attention due to a possible application in drug discovery and development. Using nuclear magnetic resonance (NMR) spectroscopy, we found that a tripeptide VVV binds to the PDZ domain of Dvl, which is a key component involved in Wnt signaling. Using a computational approach calculating the binding free energy of the complexes of the Dvl PDZ domain and each of the tripeptides VXV (X: any amino acid residue except Pro), we found that a tripeptide VWV had the highest binding affinity. Consistent with the computational result, experimental results showed that the binding of the tripeptide VWV to the Dvl PDZ domain was stronger than that of the tripeptide VVV. The binding affinity of the tripeptide VWV was comparable to that of the organic molecule NSC668036, which was the first identified Dvl PDZ inhibitor. The three-dimensional structure of the complex Dvl1 PDZ/VWV was determined to investigate the role of the energetically favorable W(-1) residue in binding. These interactions were also explored by using molecular dynamic simulation and the molecular mechanics Poisson-Boltzmann surface area method. Taken together, these two tripeptides may be used as modulators of Wnt signaling or as a scaffold to optimize an antagonist for targeting Dvl1 PDZ protein-protein interaction.

Citing Articles

Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling.

Wang L, Zhu R, Wen Z, Fan H, Norwood-Jackson T, Jathan D Cells. 2024; 13(22).

PMID: 39594618 PMC: 11592973. DOI: 10.3390/cells13221870.

Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling.

Kamdem N, Roske Y, Kovalskyy D, Platonov M, Balinskyi O, Kreuchwig A Magn Reson (Gott). 2023; 2(1):355-374.

PMID: 37904770 PMC: 10539800. DOI: 10.5194/mr-2-355-2021.

Can We Pharmacologically Target Dishevelled: The Key Signal Transducer in the Wnt Pathways?.

Micka M, Bryja V Handb Exp Pharmacol. 2021; 269:117-135.

PMID: 34382124 DOI: 10.1007/164_2021_527.

Discovery of Potent Disheveled/Dvl Inhibitors Using Virtual Screening Optimized With NMR-Based Docking Performance Index.

Hori K, Ajioka K, Goda N, Shindo A, Takagishi M, Tenno T Front Pharmacol. 2018; 9:983.

PMID: 30233369 PMC: 6134994. DOI: 10.3389/fphar.2018.00983.

Modulating the wnt signaling pathway with small molecules.

Tran F, Zheng J Protein Sci. 2017; 26(4):650-661.

PMID: 28120389 PMC: 5368067. DOI: 10.1002/pro.3122.

References

Yao Z, Lu R, Jia J, Zhao P, Yang J, Zheng M . The effect of tripeptide tyroserleutide (YSL) on animal models of hepatocarcinoma. Peptides. 2005; 27(6):1167-72. DOI: 10.1016/j.peptides.2005.02.026. View

Uematsu K, He B, You L, Xu Z, McCormick F, Jablons D . Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene. 2003; 22(46):7218-21. DOI: 10.1038/sj.onc.1206817. View

Loughlin W, Tyndall J, Glenn M, Fairlie D . Beta-strand mimetics. Chem Rev. 2004; 104(12):6085-117. DOI: 10.1021/cr040648k. View

Wallingford J, Habas R . The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development. 2005; 132(20):4421-36. DOI: 10.1242/dev.02068. View

Wang W, Donini O, Reyes C, Kollman P . Biomolecular simulations: recent developments in force fields, simulations of enzyme catalysis, protein-ligand, protein-protein, and protein-nucleic acid noncovalent interactions. Annu Rev Biophys Biomol Struct. 2001; 30:211-43. DOI: 10.1146/annurev.biophys.30.1.211. View

Delaglio F, Grzesiek S, Vuister G, Zhu G, Pfeifer J, Bax A . NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR. 1995; 6(3):277-93. DOI: 10.1007/BF00197809. View

Wang J, Morin P, Wang W, Kollman P . Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. J Am Chem Soc. 2001; 123(22):5221-30. DOI: 10.1021/ja003834q. View

Laskowski R, Rullmannn J, MacArthur M, Kaptein R, Thornton J . AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR. 1996; 8(4):477-86. DOI: 10.1007/BF00228148. View

Charnley M, Moir A, Douglas C, Haycock J . Anti-microbial action of melanocortin peptides and identification of a novel X-Pro-D/L-Val sequence in Gram-positive and Gram-negative bacteria. Peptides. 2008; 29(6):1004-9. DOI: 10.1016/j.peptides.2008.02.004. View

10.

Wong H, Mao J, Nguyen J, Srinivas S, Zhang W, Liu B . Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway. Nat Struct Biol. 2000; 7(12):1178-84. PMC: 4381838. DOI: 10.1038/82047. View

11.

Dominguez C, Boelens R, Bonvin A . HADDOCK: a protein-protein docking approach based on biochemical or biophysical information. J Am Chem Soc. 2003; 125(7):1731-7. DOI: 10.1021/ja026939x. View

12.

Eker F, Griebenow K, Cao X, Nafie L, Schweitzer-Stenner R . Tripeptides with ionizable side chains adopt a perturbed polyproline II structure in water. Biochemistry. 2004; 43(3):613-21. DOI: 10.1021/bi035740+. View

13.

Eker F, Griebenow K, Schweitzer-Stenner R . Stable conformations of tripeptides in aqueous solution studied by UV circular dichroism spectroscopy. J Am Chem Soc. 2003; 125(27):8178-85. DOI: 10.1021/ja034625j. View

14.

Shi Z, Chen K, Liu Z, Ng A, Bracken W, Kallenbach N . Polyproline II propensities from GGXGG peptides reveal an anticorrelation with beta-sheet scales. Proc Natl Acad Sci U S A. 2005; 102(50):17964-8. PMC: 1312395. DOI: 10.1073/pnas.0507124102. View

15.

Sussman D, Klingensmith J, Salinas P, Adams P, Nusse R, Perrimon N . Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled. Dev Biol. 1994; 166(1):73-86. DOI: 10.1006/dbio.1994.1297. View

16.

Hong F, Ming L, Yi S, Zhanxia L, Yongquan W, Chi L . The antihypertensive effect of peptides: a novel alternative to drugs?. Peptides. 2008; 29(6):1062-71. DOI: 10.1016/j.peptides.2008.02.005. View

17.

Koradi R, Billeter M, Wuthrich K . MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph. 1996; 14(1):51-5, 29-32. DOI: 10.1016/0263-7855(96)00009-4. View

18.

Appleton B, Zhang Y, Wu P, Yin J, Hunziker W, Skelton N . Comparative structural analysis of the Erbin PDZ domain and the first PDZ domain of ZO-1. Insights into determinants of PDZ domain specificity. J Biol Chem. 2006; 281(31):22312-22320. DOI: 10.1074/jbc.M602901200. View

19.

Schapira M, Totrov M, Abagyan R . Prediction of the binding energy for small molecules, peptides and proteins. J Mol Recognit. 1999; 12(3):177-90. DOI: 10.1002/(SICI)1099-1352(199905/06)12:3<177::AID-JMR451>3.0.CO;2-Z. View

20.

Skelton N, Koehler M, Zobel K, Wong W, Yeh S, Pisabarro M . Origins of PDZ domain ligand specificity. Structure determination and mutagenesis of the Erbin PDZ domain. J Biol Chem. 2002; 278(9):7645-54. DOI: 10.1074/jbc.M209751200. View