Kinematic Flexibility Analysis of Active and Inactive Kinase Conformations

Abstract

AbstractProtein kinases are cellular enzymes that catalyze the transfer of phosphates from adenosine triphosphate (ATP) to their substrates. Phosphorylation regulates a multitude of cellular activities, and impaired kinase activity is frequently oncogenic. Inactive or activated forms of kinases are often classified into specific conformations of their activation loops and surrounding areas. This information is valuable for developing potent and selective kinase inhibitors. However, these classification schemes ignore how the dynamics of kinases can differ between states. Here, we apply kinematic flexibility analysis (KFA) to characterize differences in the degree of rigidification between active and inactive states for a large set of kinases in the Protein Data Bank (PDB). Overall, we found that the activation loop in the active state rigidifies kinase conformations, while this effect is less pronounced in the inactive state.