ArticleACS chemical biology2022
Subsite Ligand Recognition and Cooperativity in the TPP Riboswitch: Implications for Fragment-Linking in RNA Ligand Discovery.
Article in ACS chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- Comparative Evaluation of Explicit Solvent Models for RNA-Ligand Docking.Journal of chemical information and modeling · 2026Article
- Opportunities for Riboswitch Inhibition by Targeting Co-Transcriptional RNA Folding Events.International journal of molecular sciences · 2024Review
- Unusual Ni⋯Ni interaction in Ni(ii) complexes as potential inhibitors for the development of new anti-SARS-CoV-2 Omicron drugs.RSC medicinal chemistry · 2024Article
- 2'-OH as a universal handle for studying intracellular RNAs.Cell chemical biology · 2024Review
- Investigation of Simultaneous and Sequential Cooperative Homotropic Inhibitor Binding to the Catalytic Chamber of SARS-CoV-2 RNA-dependent RNA Polymerase (RdRp).Cell biochemistry and biophysics · 2023Article
- Crystal structure of Escherichia coli thiamine pyrophosphate-sensing riboswitch in the apo state.Structure (London, England : 1993) · 2023Article
- Innovations in targeting RNA by fragment-based ligand discovery.Current opinion in structural biology · 2023Review
- Targeting RNA with small molecules: lessons learned from Xist RNA.RNA (New York, N.Y.) · 2023Article
- Characterizing RNA-binding ligands on structures, chemical information, binding affinity and drug-likeness.RNA biology · 2023Article
- How does RNA fold dynamically?Journal of molecular biology · 2022Review
- RNA-Ligand Interactions Quantified by Surface Plasmon Resonance with Reference Subtraction.Biochemistry · 2022Article
- SHAPE-enabled fragment-based ligand discovery for RNA.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Brief considerations on targeting RNA with small molecules.Faculty reviews · 2022Review
- An overview of structural approaches to study therapeutic RNAs.Frontiers in molecular biosciences · 2022Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
RNA molecules can show high levels of cooperativity in their global folding and interactions with divalent ions. However, cooperativity at individual ligand-RNA interaction sites remains poorly understood. Here, we investigated the binding of thiamine and methylene diphosphonic acid (MDP, a soluble structural analogue of pyrophosphate) to the thiamine pyrophosphate riboswitch. These ligands each bind weakly at proximal subsites, with 10 μM and 1 mM affinities, respectively. The affinity of MDP moderately improves when thiamine or thiamine-like fragments are pre-bound to the RNA. Covalent linking of thiamine and MDP substantially increases riboswitch binding to a notable high affinity of 20 nM. Crystal structures and single-molecule correlated chemical probing revealed favorable induced fit effects upon binding of individual ligands and, unexpectedly, a substantial thermodynamically unfavorable RNA structural rearrangement upon binding of the linked thiamine-MDP ligand. Thus, linking of two ligands of modest affinity, accompanied by an unfavorable structural rearrangement, still yields a potent linked RNA-binding compound. Since complex ligands often bind riboswitches and other RNAs at proximal subsites, principles derived from this work inform and support fragment-linking strategies for identifying small molecules that interact with RNA specifically and with high affinity.
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