Accent Therapeutics, 1050 Waltham Street, Lexington, MA 02421, USA.
Acta Crystallogr D Struct Biol. 2023 Nov 1;79(Pt 11):980-991. doi: 10.1107/S2059798323007611. Epub 2023 Oct 20.
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.
DHX9 是一种 DExH-box RNA 解旋酶，在转录、翻译、RNA 加工和 DNA 复制调控中具有多种功能。DHX9 最近成为肿瘤学的一个有前途的靶点，但迄今为止，还没有发表哺乳动物结构。本文报道了与人、犬和猫 DHX9 结合 ADP 的晶体结构。这三种哺乳动物 DHX9 结构具有相同的结构折叠。此外，DHX9 的整体结构和各个结构域结构与之前在与 RNA 和 ATP 过渡态类似物结合的果蝇同源物 MLE 高度保守。由于结合底物和全局结构域取向的差异，DHX9 与 MLE 结构之间的局部环构象和 dsRNA 结合结构域 2（dsRBD2）的占有率不同。结构变化的综合影响极大地改变了 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提供了一个潜在的工具。
