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.
Freund
C
C
Protein Engineering, Molecular Modeling Group, FU and FMP Berlin, Robert-Rössle-Str. 10, Berlin, Germany. freund@fmp-berlin.de
Schmalz
H-G
HG
Sticht
J
J
Kühne
R
R
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D016503:Drug Delivery Systems; D006801:Humans; D008024:Ligands; D011392:Proline / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
D008024:Ligands; D011392:Proline