SPECIFIC INTERACTIONS OUTSIDE THE PROLINE-RICH CORE OF 2 CLASSES OF SRC-HOMOLOGY-3 LIGANDS

Two dodecapeptides belonging to distinct classes of Src homology 3 (SH 3) ligands and selected from biased phage display libraries were used to investigate interactions between a specificity pocket in the Src SH 3 domain and ligand residues flanking the proline-rich core, The solut ion structures of c-Src SH3 complexed with these peptides were solved by NMR. In addition to a proline-rich, polyproline type II helix-formi ng core, the class I and II ligands each possesses a flanking sequence that occupies a large pocket between the RT and n-Src loops of the SH 3 domain. Structural and mutational analyses illustrate how the two cl asses of SH3 ligands exploit a specificity pocket on the receptor diff erently to increase binding affinity and specificity.