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A chemical probe based on the PreQ1 metabolite enables transcriptome-wide mapping of binding sites.

<div class='caption-title'>Synthetic route for the preparation of chemical probes.</div>
<div class='caption-title'>Biochemical optimization of photocrosslinking and competition experiments to evaluate the specificity of compound 11 for the Ss-preQ1-RS aptamer.</div>
<div class='caption-title'>Probe 11 selectively crosslinks to guanosine bases in the PreQ1 aptamer.</div>
Balaratnam S, Rhodes C, Bume DD, Connelly C, Lai CC, Kelley JA, Yazdani K, Homan PJ, Incarnato D, Numata T, Schneekloth JS
OpenAccess logo Nat Commun 12 5856 (2021)
Cited: 9 times
EuropePMC logo PMID: 34615874

Abstract

The role of metabolite-responsive riboswitches in regulating gene expression in bacteria is well known and makes them useful systems for the study of RNA-small molecule interactions. Here, we study the PreQ1 riboswitch system, assessing sixteen diverse PreQ1-derived probes for their ability to selectively modify the class-I PreQ1 riboswitch aptamer covalently. For the most active probe (11), a diazirine-based photocrosslinking analog of PreQ1, X-ray crystallography and gel-based competition assays demonstrated the mode of binding of the ligand to the aptamer, and functional assays demonstrated that the probe retains activity against the full riboswitch. Transcriptome-wide mapping using Chem-CLIP revealed a highly selective interaction between the bacterial aptamer and the probe. In addition, a small number of RNA targets in endogenous human transcripts were found to bind specifically to 11, providing evidence for candidate PreQ1 aptamers in human RNA. This work demonstrates a stark influence of linker chemistry and structure on the ability of molecules to crosslink RNA, reveals that the PreQ1 aptamer/ligand pair are broadly useful for chemical biology applications, and provides insights into how PreQ1, which is similar in structure to guanine, interacts with human RNAs.

Reviews - 7e9e mentioned but not cited (1)

  1. Brief considerations on targeting RNA with small molecules. Vicens Q, Westhof E. Fac Rev 11 39 (2022)


Reviews citing this publication (3)

  1. Targeting RNA structures with small molecules. Childs-Disney JL, Yang X, Gibaut QMR, Tong Y, Batey RT, Disney MD. Nat Rev Drug Discov 21 736-762 (2022)
  2. Contemporary Progress and Opportunities in RNA-Targeted Drug Discovery. Garner AL. ACS Med Chem Lett 14 251-259 (2023)
  3. Real-Time Assessment of Intracellular Metabolites in Single Cells through RNA-Based Sensors. Ortega AD. Biomolecules 13 765 (2023)

Articles citing this publication (5)

  1. Transcriptome-Wide Mapping of Small-Molecule RNA-Binding Sites in Cells Informs an Isoform-Specific Degrader of QSOX1 mRNA. Tong Y, Gibaut QMR, Rouse W, Childs-Disney JL, Suresh BM, Abegg D, Choudhary S, Akahori Y, Adibekian A, Moss WN, Disney MD. J Am Chem Soc 144 11620-11625 (2022)
  2. Affinity-Based Profiling of the Flavin Mononucleotide Riboswitch. Crielaard S, Maassen R, Vosman T, Rempkens I, Velema WA. J Am Chem Soc 144 10462-10470 (2022)
  3. Pervasive transcriptome interactions of protein-targeted drugs. Fang L, Velema WA, Lee Y, Xiao L, Mohsen MG, Kietrys AM, Kool ET. Nat Chem 15 1374-1383 (2023)
  4. Non-covalent dyes in microscale thermophoresis for studying RNA ligand interactions and modifications. Kallert E, Behrendt M, Frey A, Kersten C, Barthels F. Chem Sci 14 9827-9837 (2023)
  5. Transcriptome-Wide Studies of RNA-Targeted Small Molecules Provide a Simple and Selective r(CUG)exp Degrader in Myotonic Dystrophy. Gibaut QMR, Bush JA, Tong Y, Baisden JT, Taghavi A, Olafson H, Yao X, Childs-Disney JL, Wang ET, Disney MD. ACS Cent Sci 9 1342-1353 (2023)


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