Control of Protein−Protein Interactions: Structure-Based Discovery of Low Molecular Weight Inhibitors of the Interactions between Pin1 WW Domain and Phosphopeptides

Abstract

Interactions involving phosphorylated Ser/Thr-Pro motifs in proteins play a key role in numerous regulatory processes in the cell. Here, we investigate potential ligands of the WW binding domain of Pin1 in order to inhibit protein−protein interactions between Pin1 and phosphopeptides. Our structure-based strategy implies the synthesis of analogues of the Ac-Thr(PO₃H₂)-Pro-NH₂ dipeptide and relies on high resolution NMR spectroscopy to accurately measure the affinity constants even in the high micromolar range.