Identification of tripeptides recognized by the PDZ domain of Dishevelled.
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.
Lee
Ho-Jin
HJ
Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Wang
Nick X
NX
Shao
Youming
Y
Zheng
Jie J
JJ
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000072261:Dishevelled Proteins; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D054731:PDZ Domains; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D009842:Oligopeptides; D010750:Phosphoproteins