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 used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) synergistically generate 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 effects of various activating or inhibiting stimuli on Abl kinase activity. The data provide a mechanistic basis explaining genetic observations and reveal a previously unknown activator region within Abl. Our findings show that drug-resistance 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.

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Abl激酶的变构调节中的能量格局的原子视图

蛋白激酶的活性通常通过信号结构域以分子内方式调节，所述信号结构域具有几个磷酸化或蛋白对接位点。激酶如何整合这种独特的结合和信号转导事件以调节其活性尚不清楚，尤其是在定量方面。我们使用NMR光谱来显示Abl调节模块（RM）中的结构元素如何协同产生多层变构机制，从而使Abl激酶能够作为精细调节的开关起作用。我们解剖了调节机制的结构和能量学，以精确测量各种激活或抑制刺激对Abl激酶活性的影响。数据提供了解释遗传学观察的机制基础，并揭示了Abl中以前未知的激活子区域。