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Published on: November 1, 2012
Crystal structures of the DExH-box RNA helicase DHX9
Young Tae Lee1, E Allen Sickmier1, Simina Grigoriu1
1Accent Therapeutics, 1050 Waltham Street, Lexington, MA 02421, USA.
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.
Insights
Crystal structures of mammalian DHX9 (a DExH-box RNA helicase) reveal conserved folds and altered RNA-binding channels compared to its Drosophila orthologue, offering insights into helicase states and drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- DHX9 (DExH-box RNA helicase) plays crucial roles in gene expression and DNA replication.
- DHX9 is a potential therapeutic target in oncology.
- No mammalian DHX9 structures were previously available.
Purpose of the Study:
- To determine the crystal structures of mammalian DHX9.
- To compare the structure of mammalian DHX9 with its Drosophila orthologue, MLE.
- To provide a structural basis for understanding DHX9 function and for drug design.
Main Methods:
- X-ray crystallography was used to solve the structures of human, dog, and cat DHX9 bound to ADP.
- Structural comparisons were made between mammalian DHX9 and Drosophila MLE.
Main Results:
- Identical structural folds were observed across human, dog, and cat DHX9.
- Mammalian DHX9 shares conserved architecture with Drosophila MLE.
- Differences in domain orientation and dsRNA-binding domain 2 (dsRBD2) occupancy alter the RNA-binding channel, suggesting distinct active and inactive states.
Conclusions:
- The determined mammalian DHX9 structures are highly conserved.
- Structural variations provide insights into the dynamic states of the helicase.
- These structures serve as a foundation for structure-based drug design targeting DHX9 in oncology.
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