Xiong Yuqing, Zeng Juan, Xia Fei, Cui Qiang, Deng Xianming, Xu Xin
School of Chemistry and Molecular Engineering, NYU-ECNU Center for Computational Chemistry at NYU Shanghai, East China Normal University, Shanghai, China.
School of Biomedical Engineering, Guangdong Medical University, Dongguan, China.
J Comput Chem. 2022 May 15;43(13):906-916. doi: 10.1002/jcc.26846. Epub 2022 Mar 24.
The human Son of Sevenless (SOS) activates the signal-transduction protein Ras by forming the complex SOS·Ras and accelerating the guanosine triphosphate (GTP) exchange in Ras. Inhibition of SOS·Ras could regulate the function of Ras in cells and has emerged as an effective strategy for battling Ras related cancers. A key factor to the success of this approach is to understand the conformational change of Ras during the GTP exchange process. In this study, we perform an extensive molecular dynamics simulation to characterize the specific conformations of Ras without and with guanine nucleotide exchange factors (GEFs) of SOS, especially for the substates of State 1 of HRasGTP∙Mg . The potent binding pockets on the surfaces of the RasGDP∙Mg , the S1.1 and S1.2 substates in State 1 of RasGTP∙Mg and the ternary complexes with SOS are predicted, including the binding sites of other domains of SOS. These findings help to obtain a more thorough understanding of Ras functions in the GTP cycling process and provide a structural foundation for future drug design.
人类七号无节制蛋白（SOS）通过形成SOS·Ras复合物并加速Ras中的鸟苷三磷酸（GTP）交换来激活信号转导蛋白Ras。抑制SOS·Ras可以调节细胞中Ras的功能，并已成为对抗Ras相关癌症的有效策略。该方法成功的一个关键因素是了解GTP交换过程中Ras的构象变化。在本研究中，我们进行了广泛的分子动力学模拟，以表征有无SOS鸟嘌呤核苷酸交换因子（GEF）时Ras的特定构象，特别是针对HRasGTP∙Mg状态1的亚状态。预测了RasGDP∙Mg、RasGTP∙Mg状态1中的S1.1和S1.2亚状态以及与SOS的三元复合物表面上的有效结合口袋，包括SOS其他结构域的结合位点。这些发现有助于更全面地了解Ras在GTP循环过程中的功能，并为未来的药物设计提供结构基础。
