Ras 相关的 C3 肉毒杆菌毒素底物 1 (Rac1) 是属于 Rho 家族的一种小型 GTP 酶。它作为二元分子开关调节多种细胞功能，包括细胞粘附和迁移。 Rac1 中 P29S 突变导致的功能障碍增加了 Rac1 激活形式的稳定性。这种持续的激活可以驱动与癌症相关的异常细胞过程，例如细胞增殖、存活和迁移。因此，寻找能够抑制该蛋白突变形式的抑制剂非常重要。大黄酸是一种具有多种药理特性的天然化合物，已对其与 Rac1 的关系进行了研究。然而，大黄酸和 Rac1 之间的具体相互作用尚未得到研究。在这项研究中，我们利用分子动力学模拟研究了天然化合物大黄酸作为两种 Rac1 形式（野生型和 P29S 突变）抑制剂的潜力。结果表明，P29S 突变导致 Rac1 蛋白的结构变化，从而使大黄酸更容易接近活性位点。此外，大黄酸与突变体Rac1的结合能比天然蛋白更负。因此，看来大黄酸对 Rac1 蛋白的 P29S 突变形式具有更好的抑制作用。版权所有 © 2024 Etebar, Hamidi, Naderpour, Abouali, Hamidi, Hajipour-Verdom, Zali, Alipour 和 Rahimzadegan。

Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase belonging to the Rho family. It acts as a binary molecular switch regulating several cellular functions, including cell adhesion and migration. Malfunctions due to the P29S mutation in Rac1 increase the stability of the activated form of Rac1. This sustained activation can drive aberrant cellular processes associated with cancer, such as cell proliferation, survival, and migration. Therefore, finding an inhibitor that can inhibit the mutant form of the protein is very important. Rhein, a natural compound with diverse pharmacological properties, has been studied in relation to Rac1. However, specific interactions between Rhein and Rac1 have not been examined. In this study, we investigated the potential of Rhein, a natural compound, as an inhibitor of two forms of Rac1: the wild type and the P29S mutation, using molecular dynamics simulations. Results indicated that the P29S mutation led to structural changes in the Rac1 protein, which resulted in greater accessibility of the Rhein to the active site. In addition, the binding energy of Rhein to mutant Rac1 was more negative than the native protein. Therefore, it seems that the Rhein has a better inhibitory effect on the P29S-mutated form of the Rac1 protein.Copyright © 2024 Etebar, Hamidi, Naderpour, Abouali, Hamidi, Hajipour-Verdom, Zali, Alipour and Rahimzadegan.