engleski

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, secondary metabolite of herbal plants was discovered as 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 non-competitive mechanism of inhibition by rosmarinic acid. This indicates that rosmarinic acid binds to the second “non-ATP” binding site of the Fyn tyrosine kinase.

Fyn; rosmarinic acid; staurosporine; tyrosine kinase; homology modeling; Composer; GOLD; FlexX; ELISA

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