Atomic view of the energy landscape in the allosteric regulation of Abl kinase

The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We have used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) form synergistically a multilayered allosteric mechanism that enables Abl kinase to function as a finely-tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effect of various stimuli, activating or inhibiting, on the Abl kinase activity. The data provide the mechanistic basis for explaining genetic observations and reveal a novel activator region within Abl. Our findings show that drug-resistant mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.