Cell division control protein 42 homolog (Cdc42), which controls a variety of cellular functions including rearrangements of the cell cytoskeleton, cell differentiation and proliferation, is a potential cancer therapeutic target. As an endogenous negative regulator of Cdc42, the Rho GDP dissociation inhibitor 1 (RhoGDI1) can prevent the GDP/GTP exchange of Cdc42 to maintain Cdc42 into an inactive state. To investigate the inhibition mechanism of Cdc42 through RhoGDI1 at the atomic level, we performed molecular dynamics (MD) simulations. Without RhoGDI1, Cdc42 has more flexible conformations, especially in switch regions which are vital for binding GDP/GTP and regulators. In the presence of RhoGDI1, it not only can change the intramolecular interactions of Cdc42 but also can maintain the switch regions into a closed conformation through extensive interactions with Cdc42. These results which are consistent with findings of biochemical and mutational studies provide deep structural insights into the inhibition mechanisms of Cdc42 by RhoGDI1. These findings are beneficial for the development of novel therapies targeting Cdc42-related cancers.

细胞分裂控制蛋白 42 同源物 (Cdc42) 控制多种细胞功能，包括细胞骨架重排、细胞分化和增殖，是潜在的癌症治疗靶点。作为Cdc42的内源性负调节因子，Rho GDP解离抑制剂1（RhoGDI1）可以阻止Cdc42的GDP/GTP交换，从而维持Cdc42处于非活性状态。为了在原子水平上研究 RhoGDI1 对 Cdc42 的抑制机制，我们进行了分子动力学 (MD) 模拟。没有 RhoGDI1，Cdc42 具有更灵活的构象，特别是在对于结合 GDP/GTP 和调节器至关重要的开关区域。在RhoGDI1存在的情况下，它不仅可以改变Cdc42的分子内相互作用，而且可以通过与Cdc42的广泛相互作用将开关区域维持为闭合构象。这些结果与生化和突变研究的结果一致，为 RhoGDI1 对 Cdc42 的抑制机制提供了深入的结构见解。这些发现有利于开发针对 Cdc42 相关癌症的新疗法。