Function and evolution of B-Raf loop dynamics relevant to cancer recurrence under drug inhibition
Function and evolution of B-Raf loop dynamics relevant to cancer recurrence under drug inhibition
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DOI：
10.1080/07391102.2020.1815578
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发表时间：
2020-09-06
影响因子：
4.4
通讯作者：
Hudson, Andre O.
中科院分区：
文献类型：
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作者：
Babbitt, Gregory A.;Lynch, Miranda L.;Hudson, Andre O.
B-Raf 蛋白激酶结构域的致癌突变长期以来一直与涉及 MAPK 通路的癌症相关。 B-Raf 中的一种组成型 MAPK 激活突变，即发生在苏氨酸磷酸化 (T599) 位点附近的 V600E（缬氨酸至谷氨酸）替换，发生在许多类型的癌症中，并且存在于大部分某些癌症中，例如黑色素瘤。由于已知 ATP 结合活性和 V600E 突变都会改变 B-Raf ATP 结合域中激活环的物理行为，因此该系统特别适合对模拟各种遗传和药物类别变体的分子动力学模拟进行比较分析。在这里，我们利用机器学习来识别功能保守的蛋白质动力学，以比较四种 B-Raf 抑制剂的结合相互作用如何影响控制 ATP 激活的功能环动力学。我们证明，针对 B-Raf 的药物开发已逐渐转向 ATP 竞争性抑制剂，这些抑制剂表现出不太倾向于模仿与 ATP 激活相关的功能保守的动态变化，并导致过度激活的副作用（即在没有二次突变的情况下诱导非肿瘤细胞中的 MAPK 激活）。我们比较了 V600E 和其他导致 B-Raf 调节环路突变的致敏和耐药性的功能动态影响，确认了这些区域中低突变耐受性的位点。最后，我们在进化背景下研究了 B-Raf 环动力学的 V600E 敏感性，证明虽然敏感性在原始真核生物中有着古老的起源，但它在早期有颌脊椎动物进化过程中也随之增加。拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯
Oncogenic mutations in the kinase domain of the B-Raf protein have long been associated with cancers involving the MAPK pathway. One constitutive MAPK activating mutation in B-Raf, the V600E (valine to glutamate) replacement occurring adjacent to a site of threonine phosphorylation (T599) occurs in many types of cancer, and in a large percentage of certain cancers, such as melanoma. Because ATP binding activity and the V600E mutation are both known to alter the physical behavior of the activation loop in the B-Raf ATP binding domain, this system is especially amenable to comparative analyses of molecular dynamics simulations modeling various genetic and drug class variants. Here, we employ machine learning enabled identification of functionally conserved protein dynamics to compare how the binding interactions of four B-Raf inhibitors impact the functional loop dynamics controlling ATP activation. We demonstrate that drug development targeting B-Raf has progressively moved towards ATP competitive inhibitors that demonstrate less tendency to mimic the functionally conserved dynamic changes associated with ATP activation and leading to the side effect of hyperactivation (i.e. inducing MAPK activation in non-tumorous cells in the absence of secondary mutation). We compare the functional dynamic impacts of V600E and other sensitizing and drug resistance causing mutations in the regulatory loops of B-Raf, confirming sites of low mutational tolerance in these regions. Lastly, we investigate V600E sensitivity of B-Raf loop dynamics in an evolutionary context, demonstrating that while sensitivity has an ancient origin with primitive eukaryotes, it was also secondarily increased during early jawed vertebrate evolution. Communicated by Ramaswamy H. Sarma