Proline Rich Sequence Recognition Domains PRD Ligands Function and Inhibition

C. Freund(*ü), H.-G. Schmalz, J. Sticht, and R. Kühne(*ü)

Contents

1 Small-Molecule Modulators of Protein-Protein Interactions (PPI) 408

2 Adaptor Domains as Key Components of PPI-Mediated

Signal Complex Formation 408

3 Properties of the PPII Helix and Principles of PRM Recognition 409

4 Molecular Features of PRD 410

5 Recognition Codes 412

6 Regulation of the Binding Function of PRDs 413

7 PRD:PRM Complexes as Targets for Pharmacological Intervention 414

7.1 SH3 Domains 415

7.2 WW Domains 417

7.3 GYF Domain 417

7.4 EVH1 Domains 418

7.5 UEV Domains 419

8 Ligand Design for PRDs 419

References 422

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.

Protein Engineering, Molecular Modeling Group, FU and FMP Berlin, Robert-Rössle-Str. 10, 13125 Berlin, Germany [email protected], [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

0 0

Post a comment