title: Homology modeling of human Fyn kinase structure: discovery of rosmarinic acid as a new Fyn kinase inhibitor and in silico study of its possible binding modes.
abstract: Tyrosine phosphorylation represents a unique signaling process that controls metabolic pathways, cell activation, growth and differentiation, membrane transport, apoptosis, neural, and other functions. We present here the three-dimensional structure of Fyn tyrosine kinase, a Src-family enzyme involved in T-cell receptor signal transduction. The structure of Fyn was modeled for homology using the Sybyl-Composer suite of programs for modeling. Procheck and Prosa II programs showed the high quality of the obtained three-dimensional model. Rosmarinic acid, a secondary metabolite of herbal plants, was discovered as a new Fyn kinase inhibitor using immunochemical and in silico methods. Two possible binding modes of rosmarinic acid were evaluated here, i.e., near to or in the ATP-binding site of kinase domain of Fyn. Enzyme kinetic experiments revealed that Fyn is inhibited by a linear-mixed noncompetitive mechanism of inhibition by rosmarinic acid. This indicates that rosmarinic acid binds to the second "non-ATP" binding site of the Fyn tyrosine kinase.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.dubravko.x.jelic@gsk.com
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: Boris
authors.initials: B
authors.lastname: Mildner
authors.forename: Sanja
authors.initials: S
authors.lastname: Kostrun
authors.forename: Krunoslav
authors.initials: K
authors.lastname: Nujić
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.forename: Ognjen
authors.initials: O
authors.lastname: Culić
authors.forename: Roberto
authors.initials: R
authors.lastname: Antolović
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002934:Cinnamates / Q000737:chemistry*; D053630:Depsides / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D000097123:Rosmarinic Acid
chemical_list: D002934:Cinnamates; D053630:Depsides; D051076:Proto-Oncogene Proteins c-fyn; D000097123:Rosmarinic Acid