Identification and structural insights into RNA motifs targeted by a CAG repeat DNA-binding small molecule.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• RNA-targeting small molecules hold therapeutic potential but their mechanisms are unclear due to limited structural data.
• Understanding RNA-small molecule interactions requires identifying model complexes for structural analysis.

Purpose of the Study:

• To identify novel RNA motifs that selectively bind to the small molecule naphthyridine-azaquinolone (NA).
• To elucidate the molecular recognition mechanism of NA with RNA targets.
• To provide structural insights into RNA-small molecule complex formation.

Main Methods:

• Surface plasmon resonance (SPR) to assess binding affinity.
• Thermal melting assays to study complex stability.
• Cold-spray ionization mass spectrometry for complex analysis.
• Solution structure determination of the NA-RNA complex.

Main Results:

• Identification of novel RNA motifs with selective binding to NA.
• Characterization of NA-RNA interactions using biophysical methods.
• Determination of the NA-RNA complex structure, revealing a unique binding mode distinct from NA-DNA interactions.

Conclusions:

• The study provides molecular-level insights into RNA-small molecule recognition.
• NA demonstrates potential as a versatile scaffold for developing novel RNA-targeting therapeutics.
• Findings advance the understanding of small molecule interactions with RNA structures.