ArticleChemistry & biology2014
Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically.
Article in Chemistry & biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 94 citations in OpenAlex.
- RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges.Pharmacological reviews · 2020Pooled it
- Comparative Evaluation of Explicit Solvent Models for RNA-Ligand Docking.Journal of chemical information and modeling · 2026Article
- Scaffold-enabled high-resolution cryo-EM structure determination of RNA.Nature communications · 2025Article
- Scaffold-enabled high-resolution cryo-EM structure determination of RNA.bioRxiv : the preprint server for biology · 2024Article
- 2'-OH as a universal handle for studying intracellular RNAs.Cell chemical biology · 2024Review
- Crystal structure of Escherichia coli thiamine pyrophosphate-sensing riboswitch in the apo state.Structure (London, England : 1993) · 2023Article
- Fragment-Based Approaches to Identify RNA Binders.Journal of medicinal chemistry · 2023Review
- Targeting Riboswitches with Beta-Axial-Substituted Cobalamins.ACS chemical biology · 2023Article
- Innovations in targeting RNA by fragment-based ligand discovery.Current opinion in structural biology · 2023Review
- X-Ray Crystallography to Study Conformational Changes in a TPP Riboswitch.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Developing New Tools to Fight Human Pathogens: A Journey through the Advances in RNA Technologies.Microorganisms · 2022Review
- Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells.Journal of the American Chemical Society · 2022Article
- SILCS-RNA: Toward a Structure-Based Drug Design Approach for Targeting RNAs with Small Molecules.Journal of chemical theory and computation · 2022Article
- Key players in regulatory RNA realm of bacteria.Biochemistry and biophysics reports · 2022Review
- SHAPE-enabled fragment-based ligand discovery for RNA.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Subsite Ligand Recognition and Cooperativity in the TPP Riboswitch: Implications for Fragment-Linking in RNA Ligand Discovery.ACS chemical biology · 2022Article
- Screening of Minimalist Noncanonical Sites in Duplex DNA and RNA Reveals Context and Motif-Selective Binding by Fluorogenic Base Probes.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- An overview of structural approaches to study therapeutic RNAs.Frontiers in molecular biosciences · 2022Review
- Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.PLoS computational biology · 2021Article
- A chemical probe based on the PreQNature communications · 2021Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Thiamine pyrophosphate (TPP) riboswitches regulate essential genes in bacteria by changing conformation upon binding intracellular TPP. Previous studies using fragment-based approaches identified small molecule "fragments" that bind this gene-regulatory mRNA domain. Crystallographic studies now show that, despite having micromolar Kds, four different fragments bind the TPP riboswitch site-specifically, occupying the pocket that recognizes the aminopyrimidine of TPP. Unexpectedly, the unoccupied site that would recognize the pyrophosphate of TPP rearranges into a structure distinct from that of the cognate complex. This idiosyncratic fragment-induced conformation, also characterized by small-angle X-ray scattering and chemical probing, represents a possible mechanism for adventitious ligand discrimination by the riboswitch, and suggests that off-pathway conformations of RNAs can be targeted for drug development. Our structures, together with previous screening studies, demonstrate the feasibility of fragment-based drug discovery against RNA targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.