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.
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.
Jelić
Dubravko
D
GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.dubravko.x.jelic@gsk.com
Mildner
Boris
B
Kostrun
Sanja
S
Nujić
Krunoslav
K
Verbanac
Donatella
D
Culić
Ognjen
O
Antolović
Roberto
R
Brandt
Wolfgang
W
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
D002934:Cinnamates; D053630:Depsides; D051076:Proto-Oncogene Proteins c-fyn; D000097123:Rosmarinic Acid