Proline-rich sequence recognition domains (PRD): ligands, function and inhibition.

Low-affinity protein-protein interactions (PPI) between domains of modular proteins and short, solvent-exposed peptide sequences within their binding partners play an essential role in intracellular signaling. An important class of PPIs comprises proline-rich motifs (PRM) that are specifically recognized by PRM-binding domains (PRD). Aromatic side chains of the PRDs define the binding pockets that often recognize individual proline residues, while flanking sequences mediate specificity. Several of these PRM:PRD interactions are associated with cellular malfunction, cancer or infectious diseases. Thus, the design of PRM:PRD inhibitors by using structure-based molecular modeling as well as peptidomimetic approaches and high-throughput screening strategies is of great pharmacological interest. In this chapter we describe the molecular basis of PRM:PRD interactions, highlight their functional role in certain cellular processes and give an overview of recent strategies of inhibitor design.