Specific Interactions Outside the Proline-Rich Core of Two Classes of Src Homology 3 Ligands

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 26; pp. 12408 - 12415
• Main Authors: Feng, S, Kasahara, C, Rickles, R J, Schreiber, S L
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 19.12.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Adaptor Proteins, Signal Transducing; Amides; Amino Acid Sequence; Animals; Atoms; Bacteriophages; Binding Sites; Biochemistry; Calorimetry; Cloning, Molecular; DNA Mutational Analysis; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Fluorescence; GRB2 Adaptor Protein; Humans; Hydrogen bonds; Libraries; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Mutagenesis; Oligopeptides - chemistry; Peptides; Proline; Protein Conformation; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein Structure, Secondary; Proteins - chemistry; Proteins - metabolism; Protons; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; src Homology Domains
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.26.12408

Two dodecapeptides belonging to distinct classes of Src homology 3 (SH3) ligands and selected from biased phage display libraries were used to investigate interactions between a specificity pocket in the Src SH3 domain and ligand residues flanking the proline-rich core. The solution structures of c-Src SH3 complexed with these peptides were solved by NMR. In addition to a proline-rich, polyproline type II helix-forming 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 SH3 domain. Structural and mutational analyses illustrate how the two classes of SH3 ligands exploit a specificity pocket on the receptor differently to increase binding affinity and specificity.