PI3K lipid kinases signal through the PI3K/Akt pathway, regulating cell growth and proliferation. While the structural features that distinguish between the active and inactive states of protein kinases are well established, that has not been the case for lipid kinases, and neither was the structural mechanism controlling the switch between the two states. Class I PI3Ks are obligate heterodimers with catalytic and regulatory subunits. Here, we analyze PI3K crystal structures. Structures with the nSH2 (inactive state) are featured by collapsed activation loop (a-loop) and an IN kinase domain helix 11 (kα11). In the active state, the a-loop is extended and kα11 in the OUT conformation. Our analysis suggests that the nSH2 domain in the regulatory subunit regulates activation, catalysis and autoinhibition through the a-loop. Inhibition, activation and catalytic scenarios are shared by class IA PI3Ks; the activation is mimicked by oncogenic mutations and the inhibition offers an allosteric inhibitor strategy.

PI3K 脂质激酶通过 PI3K/Akt 通路发出信号，调节细胞生长和增殖。虽然区分蛋白激酶的活性和非活性状态的结构特征已经确立，但脂质激酶的情况并非如此，控制两种状态之间转换的结构机制也不是。I 类 PI3K 是具有催化和调节亚基的专性异二聚体。在这里，我们分析 PI3K 晶体结构。具有 nSH2（非活性状态）的结构以折叠的激活环（a-loop）和 IN 激酶结构域螺旋 11（kα11）为特征。在活动状态下，a-loop 被扩展并且 kα11 处于 OUT 构象中。我们的分析表明，调节亚基中的 nSH2 结构域通过 a 环调节激活、催化和自抑制。抑制，IA 类 PI3K 共享活化和催化场景；致癌突变模拟了激活，并且抑制提供了变构抑制剂策略。