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Updated: Jul 12, 2026
11:34
Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
Cryptic RNA binding sites are energetically accessible and chemically addressable.
Biorxiv : the Preprint Server for Biology
|July 10, 2026
Summary
Cryptic RNA binding sites, revealed by local dynamics, are energetically accessible for ligand discovery. These sites, like those in the cobalamin riboswitch, can be targeted by small molecules, expanding RNA ligandability.
Area of Science:
- RNA structural dynamics
- Ligand discovery
- Biochemistry
Background:
- Cryptic binding sites in proteins are key for ligand discovery.
- Their energetic accessibility and role in RNA recognition are less understood.
- The cobalamin (Cbl) riboswitch serves as a model to study these phenomena.
Purpose of the Study:
- Investigate cryptic-site formation via base displacement in the Cbl riboswitch.
- Quantify the energetic costs of cryptic site formation.
- Explore the presence and accessibility of similar cryptic sites in other RNAs.
Main Methods:
- Structural analysis of the Cbl riboswitch.
- Isothermal titration calorimetry and fluorescence measurements.
- Computational conformational sampling.
- Site-directed abasic substitution.
Main Results:
- Cobalamin binding displaces an adenosine, exposing a cryptic site.
- Cryptic site formation has an energetic penalty of ~1.4 kcal mol⁻¹.
- Analogous cryptic sites were found in HIV-1 and HCV RNAs, accessible via base displacement.
- A known ligand targeted the Cbl cryptic site and bound HIV-1 and HCV RNAs.
Conclusions:
- Cryptic RNA binding sites are energetically accessible and can be targeted by ligands.
- Local conformational dynamics create ligandable cryptic sites in diverse RNAs.
- This expands the understanding of RNA conformational states relevant to drug discovery.
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