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Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure
Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. Riboswitches control the expression of essential bacterial genes and are important models for RNA-small molecule recognition. Here, we report the discovery of a class of synthetic...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445138/ https://www.ncbi.nlm.nih.gov/pubmed/30940810 http://dx.doi.org/10.1038/s41467-019-09493-3 |
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author | Connelly, Colleen M. Numata, Tomoyuki Boer, Robert E. Moon, Michelle H. Sinniah, Ranu S. Barchi, Joseph J. Ferré-D’Amaré, Adrian R. Schneekloth, John S. |
author_facet | Connelly, Colleen M. Numata, Tomoyuki Boer, Robert E. Moon, Michelle H. Sinniah, Ranu S. Barchi, Joseph J. Ferré-D’Amaré, Adrian R. Schneekloth, John S. |
author_sort | Connelly, Colleen M. |
collection | PubMed |
description | Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. Riboswitches control the expression of essential bacterial genes and are important models for RNA-small molecule recognition. Here, we report the discovery of a class of synthetic small molecules that bind to PreQ(1) riboswitch aptamers. These molecules bind specifically and reversibly to the aptamers with high affinity and induce a conformational change. Furthermore, the ligands modulate riboswitch activity through transcriptional termination despite no obvious chemical similarity to the cognate ligand. X-ray crystallographic studies reveal that the ligands share a binding site with the cognate ligand but make different contacts. Finally, alteration of the chemical structure of the ligand causes changes in the mode of RNA binding and affects regulatory function. Thus, target- and structure-based approaches can be used to identify and understand the mechanism of synthetic ligands that bind to and regulate complex, folded RNAs. |
format | Online Article Text |
id | pubmed-6445138 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64451382019-04-03 Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure Connelly, Colleen M. Numata, Tomoyuki Boer, Robert E. Moon, Michelle H. Sinniah, Ranu S. Barchi, Joseph J. Ferré-D’Amaré, Adrian R. Schneekloth, John S. Nat Commun Article Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. Riboswitches control the expression of essential bacterial genes and are important models for RNA-small molecule recognition. Here, we report the discovery of a class of synthetic small molecules that bind to PreQ(1) riboswitch aptamers. These molecules bind specifically and reversibly to the aptamers with high affinity and induce a conformational change. Furthermore, the ligands modulate riboswitch activity through transcriptional termination despite no obvious chemical similarity to the cognate ligand. X-ray crystallographic studies reveal that the ligands share a binding site with the cognate ligand but make different contacts. Finally, alteration of the chemical structure of the ligand causes changes in the mode of RNA binding and affects regulatory function. Thus, target- and structure-based approaches can be used to identify and understand the mechanism of synthetic ligands that bind to and regulate complex, folded RNAs. Nature Publishing Group UK 2019-04-02 /pmc/articles/PMC6445138/ /pubmed/30940810 http://dx.doi.org/10.1038/s41467-019-09493-3 Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Connelly, Colleen M. Numata, Tomoyuki Boer, Robert E. Moon, Michelle H. Sinniah, Ranu S. Barchi, Joseph J. Ferré-D’Amaré, Adrian R. Schneekloth, John S. Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title | Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title_full | Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title_fullStr | Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title_full_unstemmed | Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title_short | Synthetic ligands for PreQ(1) riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure |
title_sort | synthetic ligands for preq(1) riboswitches provide structural and mechanistic insights into targeting rna tertiary structure |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445138/ https://www.ncbi.nlm.nih.gov/pubmed/30940810 http://dx.doi.org/10.1038/s41467-019-09493-3 |
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