title: Acquisition of Fyn-selective SH3 domain ligands via a combinatorial library strategy.
abstract: A stepwise library-based strategy has been employed to acquire a potent ligand for the SH3 domain of Fyn, a Src kinase family member that plays a key role in T cell activation. The easily automated methodology is designed to identify potential interaction sites that circumscribe the protein/peptide binding region on the SH3 domain. The library protocol creates peptide/nonpeptide chimeras that are able to bind to these interaction sites that are otherwise inaccessible to natural amino acid residues. The peptide-derived lead and the Fyn-SH3 domain form a complex that exhibits a K(D) of 25 +/- 5 nM, approximately 1000-fold more potent than that displayed by the corresponding conventional peptide ligand. Furthermore, the lead ligand exhibits selectivity against SH3 domains derived from other Src kinases, in spite of a sequence identity of approximately 80%.
authors.affiliation: The Albert Einstein College of Medicine, Department of Biochemistry, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Haishan
authors.initials: H
authors.lastname: Li
authors.forename: David S
authors.initials: DS
authors.lastname: Lawrence
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002477:Cells; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D008024:Ligands; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011993:Recombinant Fusion Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn