Effective Disruption of Phosphoprotein−Protein Surface Interaction Using Zn(II) Dipicolylamine-Based Artificial Receptors via Two-Point Interaction

Protein phosphorylation is ubiquitously involved in living cells, and it is one of the key events
controlling protein−protein surface interactions, which are essential in signal transduction cascades. We
now report that the small molecular receptors bearing binuclear Zn(II)-Dpa can strongly bind to a bis-phosphorylated peptide in a cross-linking manner under neutral aqueous conditions when the distance
between the two Zn(II) centers can appropriately fit in that of the two phosphate groups of the phosphorylated
peptide. The binding property was quantitatively determined by ITC (isothermal titration calorimetry), induced
CD (circular dichroism), and NMR. On the basis of these findings, we demonstrated that these types of
small molecules were able to effectively disrupt the phosphoprotein−protein interaction in a phosphorylated
CTD peptide and the Pin1 WW domain, a phosphoprotein binding domain, at a micromolar level. The
strategy based on a small molecular disruptor that directly interacts with phosphoprotein is unique and
should be promising in developing a designer inhibitor for phosphoprotein−protein interaction.