DHX9 is a DExH-box RNA helicase with versatile functions in transcription, translation, RNA processing and regulation of DNA replication. DHX9 has recently emerged as a promising target for oncology, but to date no mammalian structures have been published. Here, crystal structures of human, dog and cat DHX9 bound to ADP are reported. The three mammalian DHX9 structures share identical structural folds. Additionally, the overall architecture and the individual domain structures of DHX9 are highly conserved with those of MLE, the Drosophila orthologue of DHX9 previously solved in complex with RNA and a transition-state analogue of ATP. Due to differences in the bound substrates and global domain orientations, the localized loop conformations and occupancy of dsRNA-binding domain 2 (dsRBD2) differ between the mammalian DHX9 and MLE structures. The combined effects of the structural changes considerably alter the RNA-binding channel, providing an opportunity to compare active and inactive states of the helicase. Finally, the mammalian DHX9 structures provide a potential tool for structure-based drug-design efforts.

中文翻译：

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DExH-box RNA 解旋酶 DHX9 的晶体结构

DHX9 是一种 DE x H-box RNA 解旋酶，在转录、翻译、RNA 加工和 DNA 复制调节方面具有多种功能。DHX9 最近已成为肿瘤学的一个有前途的靶标，但迄今为止尚未发表哺乳动物结构。在此，报道了与 ADP 结合的人、狗和猫 DHX9 的晶体结构。三种哺乳动物 DHX9 结构具有相同的结构折叠。此外，DHX9 的整体结构和单个结构域结构与 MLE 的结构和单个结构域结构高度保守，MLE 是DHX9 的果蝇直系同源物，之前已与 RNA 和 ATP 的过渡态类似物形成复合物。由于结合底物和整体结构域方向的差异，哺乳动物 DHX9 和 MLE 结构之间 dsRNA 结合结构域 2 (dsRBD2) 的局部环构象和占据情况不同。结构变化的综合效应极大地改变了 RNA 结合通道，为比较解旋酶的活性和非活性状态提供了机会。最后，哺乳动物 DHX9 结构为基于结构的药物设计工作提供了潜在的工具。