Crystal structures of the DExH-box RNA helicase DHX9

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.