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A small cationic probe for accurate, punctate discovery of RNA tertiary structure
Jeffery E Ehrhardt1,2, David Y Qiu1,2, Shouhong Jin1
1Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290.
Biorxiv : the Preprint Server for Biology
|September 5, 2025
Summary
Researchers discovered a new chemical method using trimethyloxonium (TMO) to identify rare RNA tertiary structures. This T-site chemistry accurately maps functional RNA cores, aiding in the analysis of complex RNA genomes.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- RNA tertiary structures are crucial for biological functions.
- Identifying these complex structures accurately remains a significant challenge.
Purpose of the Study:
- To develop a novel chemical method for discovering RNA tertiary structural motifs.
- To map functional RNA cores with high confidence across diverse RNA molecules.
Main Methods:
- Utilizing a positively-charged chemical probe, trimethyloxonium (TMO), to selectively react with electronegative pockets in RNA tertiary structures.
- Comparing TMO reactivity with uncharged dimethyl sulfate (DMS) to identify specific T-sites.
- Applying T-site chemistry to probe the dengue virus RNA genome.
Main Results:
- T-sites were identified as punctate electronegative pockets formed by nucleobase and backbone interactions.
- These T-sites precisely map to higher-order structural interactions and functional cores in various RNAs.
- Three T-sites were found in the dengue virus RNA genome, each within a functionally important replication structure.
Conclusions:
- T-site chemistry offers a high-confidence approach for discovering and analyzing functional RNA tertiary structures.
- This method is applicable to long, complex RNA molecules, including transcriptome-wide analysis.
- The findings open new avenues for understanding RNA structure-function relationships in diverse biological systems.
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