AI Article Synopsis
- DHX9 is a versatile DExH-box RNA helicase involved in various cellular processes and has potential as a cancer therapy target, though mammalian structures were previously undocumented.
- Crystal structures of DHX9 from humans, dogs, and cats were solved, revealing they share similar structural folds with the Drosophila orthologue, MLE.
- Differences in bound substrates and domain orientations lead to variations in the localized structures, affecting the RNA-binding channel and enabling comparisons of the helicase's active and inactive states, which could aid drug design.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619421 | PMC |
| http://dx.doi.org/10.1107/S2059798323007611 | DOI Listing |
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