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Proline-Rich Sequence Recognition Domains (PRD): Ligands, Function and Inhibition

  • Chapter
Protein-Protein Interactions as New Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 186))

Abstract

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.

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Authors and Affiliations

  1. Protein Engineering, Molecular Modeling Group, FU and FMP Berlin, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    C. Freund & R. Kühne

  2. Institute of Organic Chemistry, University Köln, Greinstr. 4, 50939, Köln, Germany

    H. -G. Schmalz

  3. Protein Engineering Group, FU and FMP Berlin, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    J. Sticht

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  1. C. Freund
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  3. J. Sticht
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  4. R. Kühne
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  1. Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Enno Klussmann

  2. The Vollum Institute, Oregon Health & Science University, Medical Research Bldg, Rm 322D 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA

    John Scott Ph.D.

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Freund, C., Schmalz, H.G., Sticht, J., Kühne, R. (2008). Proline-Rich Sequence Recognition Domains (PRD): Ligands, Function and Inhibition. In: Klussmann, E., Scott, J. (eds) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology, vol 186. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72843-6_17

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