Kinase activation by small conformational changes

Protein Kinases (PKs) are allosteric enzymes that play an essential role in signal transduction by regulating a variety of key cellular processes. Most PKs suffer con- formational rearrangements upon phosphorylation that strongly enhance the catalytic activity. Generally, it involves the movement of the phosphorylated loop towards the active site and the rotation of the whole C-terminal lobe. However, not all kinases un- dergo such a large configurational change: The MAPK extracellular signal-regulated protein kinases ERK1 and ERK2 achieve a 50,000 fold increase in kinase activity with only a small motion of the C-terminal region. In the present work, we used a combi- nation of molecular simulation tools to characterize the conformational landscape of ERK2 in the active (phosphorylated) and inactive (unphosphorylated) states in solu- tion in agreement with NMR experiments. We show that the chemical reaction barrier is strongly dependent on ATP conformation and that the ‘active’ -low barrier- con- figurati...