SH3 DOMAINS AND DRUG DESIGN - LIGANDS, STRUCTURE, AND BIOLOGICAL FUNCTION

The ligand binding preferences, structural features, and biological fu nction of SH3 (Src homology 3) domains are discussed. SH3 domains bind ''core'' Pro-rich peptide ligands (7-9 amino acids in length) in a po lyproline II helical conformation in a highly conserved aromatic rich patch on the protein surface (approximately 390 Angstrom(2)). The liga nds can interact with the protein in one of two orientations, dependin g on the position (N- vs C-terminal) of ligand residues binding to the SH3 selectivity pocket. Core SH3 ligands are characterized by relativ ely weak interactions (K-D=5-100 mu M) that show little binding select ivity within SH3 families. Higher affinity, more selective contiguous ligands require additional flanking residues that bind to less conserv ed portions of the SH3 surface, with corresponding increase in ligand size and complexity. In contrast to peptide ligands, protein ligands o f SH3 domains can exploit multiple discontiguous interactions to enhan ce affinity and selectivity. A protein-SH3 interaction that utilizes u nique interactions may permit the design of small high affinity SH3 li gands. At present, the extended nature of the binding site and homolog ous nature of the core binding region among SH3 domains present key ch allenges for structure-based drug design. (C) 1998 John Wiley & Sons, Inc.