Laudadio Emiliano, Mobbili Giovanna, Sorci Leonardo, Galeazzi Roberta, Minnelli Cristina
Department of Science and Engineering of Matter, Environment and Urban Planning, Marche Polytechnic University, Ancona, Italy.
Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy.
J Biomol Struct Dyn. 2023 Aug-Sep;41(14):6492-6501. doi: 10.1080/07391102.2022.2108497. Epub 2022 Aug 13.
The discovery of mutations within the kinase domain of the epidermal growth factor receptor (EGFR) gene has enabled a new era of targeted therapy in non-small cell lung cancer (NSCLC). Drugs belonging to the family of tyrosine kinase inhibitors (TKIs) are designed to bind ATP binding cleft, anyway, the occurrence of aminoacidic mutations decreases the effectiveness of the antitumoral treatment. Despite many efforts has been already made, the impact of the mutations on conformation and stability of EGFR-ATP complexes is still not fully understood. Therefore, we investigated the effect of mutations that leads to changes in Michaelis-Menten constant () using dynamic docking simulations. We focused on six different EGFR forms in relation to different mutation states, then we found a good correlation between the calculated ATP affinities and values. Moreover, since dynamic switching of TK-EGFR from the inactive towards the active state is known to regulate the kinase activity, we observed that ATP induces the inwards movement of the αC-helix with the Lys745 close to Glu762 in all cases. This means that ATP binding should be the first step in promoting the conformational shift to the active state. Finally, we highlighted for the first time the key contribution of water hydrogen bond and water-bridge networks in the modulation of ATP affinity. The identified mutant-specific ATP binding patterns and conformational features could be much useful to guide cancer therapy and develop more personalized medicine. Communicated by Ramaswamy H. Sarma.
表皮生长因子受体（EGFR）基因激酶结构域内突变的发现开启了非小细胞肺癌（NSCLC）靶向治疗的新时代。酪氨酸激酶抑制剂（TKIs）家族的药物旨在结合ATP结合裂隙，然而，氨基酸突变的出现会降低抗肿瘤治疗的效果。尽管已经做出了许多努力，但突变对EGFR-ATP复合物构象和稳定性的影响仍未完全了解。因此，我们使用动态对接模拟研究了导致米氏常数（）变化的突变的影响。我们关注了与不同突变状态相关的六种不同EGFR形式，然后发现计算出的ATP亲和力与值之间存在良好的相关性。此外，由于已知TK-EGFR从无活性状态向活性状态的动态转换会调节激酶活性，我们观察到在所有情况下，ATP都会诱导αC螺旋向内移动，使赖氨酸745靠近谷氨酸762。这意味着ATP结合应该是促进向活性状态构象转变的第一步。最后，我们首次强调了水氢键和水桥网络在调节ATP亲和力中的关键作用。所确定的突变体特异性ATP结合模式和构象特征可能对指导癌症治疗和开发更个性化的药物非常有用。由拉马斯瓦米·H·萨尔马传达。
