Design, synthesis, structure and binding properties of PDZ binding, cyclic β-finger peptides

Protein interaction domains (PIDs) play a critical role in signal transduction. One PID of great interest is the PDZ domain, a 100 amino-acid-residue domain. Most PDZ domains recognize short, C-terminal peptide motives. In the heterodimer of the nNOS-PDZ domain and the α-syntrophin-PDZ domain, however, one PDZ domain forms a β-finger that binds to the other PDZ domain. We show here that cyclic peptides derived from the β-finger of the nNOS-PDZ domain can bind the syntrophin-PDZ domain in the same manner as the whole domain. The structure of three “finger-peptides” of different size has been determined and the binding investigated using calorimetry and NMR-titration experiments.