Src kinase activation: A switched electrostatic network

Authors

  • Elif Ozkirimli,

    1. Medicinal Chemistry and Molecular Pharmacology Department, Markey Center for Structural Biology and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-2091, USA
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  • Carol Beth Post

    Corresponding author
    1. Medicinal Chemistry and Molecular Pharmacology Department, Markey Center for Structural Biology and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-2091, USA
    • Carol Beth Post, Medicinal Chemistry and Molecular Pharmacology Department, Markey Center for Structural Biology and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907-2091, USA; fax: (765) 496-1189.
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Abstract

Src tyrosine kinases are essential in numerous cell signaling pathways, and improper functioning of these enzymes has been implicated in many diseases. The activity of Src kinases is regulated by conformational activation, which involves several structural changes within the catalytic domain (CD): the orientation of two lobes of CD; rearrangement of the activation loop (A-loop); and movement of an α-helix (αC), which is located at the interface between the two lobes, into or away from the catalytic cleft. Conformational activation was investigated using biased molecular dynamics to explore the transition pathway between the active and the down-regulated conformation of CD for the Src-kinase family member Lyn kinase, and to gain insight into the interdependence of these changes. Lobe opening is observed to be a facile motion, whereas movement of the A-loop motion is more complex requiring secondary structure changes as well as communication with αC. A key result is that the conformational transition involves a switch in an electrostatic network of six polar residues between the active and the down-regulated conformations. The exchange between interactions links the three main motions of the CD. Kinetic experiments that would demonstrate the contribution of the switched electrostatic network to the enzyme mechanism are proposed. Possible implications for regulation conferred by interdomain interactions are also discussed.

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