State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Nucleic Acids Res. 2023 Jul 5;51(W1):W129-W133. doi: 10.1093/nar/gkad295.
Driver mutations can contribute to the initial processes of cancer, and their identification is crucial for understanding tumorigenesis as well as for molecular drug discovery and development. Allostery regulates protein function away from the functional regions at an allosteric site. In addition to the known effects of mutations around functional sites, mutations at allosteric sites have been associated with protein structure, dynamics, and energy communication. As a result, identifying driver mutations at allosteric sites will be beneficial for deciphering the mechanisms of cancer and developing allosteric drugs. In this study, we provided a platform called DeepAlloDriver to predict driver mutations using a deep learning method that exhibited >93% accuracy and precision. Using this server, we found that a missense mutation in RRAS2 (Gln72 to Leu) might serve as an allosteric driver of tumorigenesis, revealing the mechanism of the mutation in knock-in mice and cancer patients. Overall, DeepAlloDriver would facilitate the elucidation of the mechanisms underlying cancer progression and help prioritize cancer therapeutic targets. The web server is freely available at: https://mdl.shsmu.edu.cn/DeepAlloDriver.
驱动突变可促成癌症的初始进程，鉴定驱动突变对于理解肿瘤发生、分子药物发现和开发至关重要。变构作用可调节远离功能区域的蛋白质功能，在变构部位的突变除了已知的功能部位的影响外，还与蛋白质结构、动力学和能量传递有关。因此，鉴定变构部位的驱动突变将有助于破译癌症发生的机制并开发变构药物。在这项研究中，我们提供了一个名为 DeepAlloDriver 的平台，该平台使用深度学习方法预测驱动突变，准确率和精度均>93%。使用该服务器，我们发现 RRAS2（Q72L）中的错义突变可能是肿瘤发生的变构驱动因素，揭示了突变在基因敲入小鼠和癌症患者中的机制。总的来说，DeepAlloDriver 将有助于阐明癌症进展的机制，并有助于确定癌症治疗靶点的优先级。该网络服务器可免费在：https://mdl.shsmu.edu.cn/DeepAlloDriver 获得。
