title: Encodable activators of SRC family kinases.
abstract: There is considerable current interest in the design of encodable molecules that regulate intracellular protein circuitry and/or activity, ideally with a high level of specificity. Src homology 3 (SH3) domains are ubiquitous components of multidomain signaling proteins, including many kinases, and are attractive drug targets because of the important role their interactions play in diseases as diverse as cancer, osteoporosis, and inflammation. Here we describe a set of miniature proteins that recognize distinct SH3 domains from Src family kinases with high affinity. Three of these molecules discriminate effectively between the SH3 domains of Src and Fyn, which are expressed ubiquitously, and two of these three activate Hck kinase with potencies that rival HIV Nef, one of the most potent kinase activators known. These results suggest that miniature proteins represent a viable, encodable strategy for selective activation of Src family kinases in a variety of cell types.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Crystal D
authors.initials: CD
authors.lastname: Zellefrow
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Griffiths
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Saha
authors.forename: Abby M
authors.initials: AM
authors.lastname: Hodges
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Goodman
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kritzer
authors.forename: Alanna
authors.initials: A
authors.lastname: Schepartz
mesh_terms: D000595:Amino Acid Sequence; D004789:Enzyme Activation; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry*
chemical_list: D010455:Peptides; D011506:Proteins; D019061:src-Family Kinases