PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations of PI3Kα and uncover, for the first time, the free energy landscape of the E545K PI3Kα mutant. We reveal the mechanism by which E545K leads to PI3Kα activation in atomic-level detail, which is considerably more complex than previously thought.

中文翻译：

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阐明 E545K 突变对 PI3Kα 激酶的影响

PI3Kα 控制多个细胞过程，其异常信号与肿瘤发生有关。其热点突变之一，E545K，增加了 PI3Kα 脂质激酶活性，但其作用模式仅被部分了解。在这里，我们对 PI3Kα 进行了有偏和无偏的分子动力学模拟，并首次揭示了 E545K PI3Kα 突变体的自由能景观。我们揭示了 E545K 在原子级细节中导致 PI3Kα 激活的机制，这比以前认为的要复杂得多。