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Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses

Coronaviruses (CoVs) use −1 programmed ribosomal frameshifting stimulated by RNA pseudoknots in the viral genome to control expression of enzymes essential for replication, making CoV pseudoknots a promising target for anti-coronaviral drugs. Bats represent one of the largest reservoirs of CoVs and...

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Autores principales: Sekar, Rohith Vedhthaanth, Oliva, Patricia J., Woodside, Michael T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234561/
https://www.ncbi.nlm.nih.gov/pubmed/37205708
http://dx.doi.org/10.1371/journal.pcbi.1011124
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author Sekar, Rohith Vedhthaanth
Oliva, Patricia J.
Woodside, Michael T.
author_facet Sekar, Rohith Vedhthaanth
Oliva, Patricia J.
Woodside, Michael T.
author_sort Sekar, Rohith Vedhthaanth
collection PubMed
description Coronaviruses (CoVs) use −1 programmed ribosomal frameshifting stimulated by RNA pseudoknots in the viral genome to control expression of enzymes essential for replication, making CoV pseudoknots a promising target for anti-coronaviral drugs. Bats represent one of the largest reservoirs of CoVs and are the ultimate source of most CoVs infecting humans, including those causing SARS, MERS, and COVID-19. However, the structures of bat-CoV frameshift-stimulatory pseudoknots remain largely unexplored. Here we use a combination of blind structure prediction followed by all-atom molecular dynamics simulations to model the structures of eight pseudoknots that, together with the SARS-CoV-2 pseudoknot, are representative of the range of pseudoknot sequences in bat CoVs. We find that they all share some key qualitative features with the pseudoknot from SARS-CoV-2, notably the presence of conformers with two distinct fold topologies differing in whether or not the 5′ end of the RNA is threaded through a junction, and similar conformations for stem 1. However, they differed in the number of helices present, with half sharing the 3-helix architecture of the SARS-CoV-2 pseudoknot but two containing 4 helices and two others only 2. These structure models should be helpful for future work studying bat-CoV pseudoknots as potential therapeutic targets.
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spelling pubmed-102345612023-06-02 Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses Sekar, Rohith Vedhthaanth Oliva, Patricia J. Woodside, Michael T. PLoS Comput Biol Research Article Coronaviruses (CoVs) use −1 programmed ribosomal frameshifting stimulated by RNA pseudoknots in the viral genome to control expression of enzymes essential for replication, making CoV pseudoknots a promising target for anti-coronaviral drugs. Bats represent one of the largest reservoirs of CoVs and are the ultimate source of most CoVs infecting humans, including those causing SARS, MERS, and COVID-19. However, the structures of bat-CoV frameshift-stimulatory pseudoknots remain largely unexplored. Here we use a combination of blind structure prediction followed by all-atom molecular dynamics simulations to model the structures of eight pseudoknots that, together with the SARS-CoV-2 pseudoknot, are representative of the range of pseudoknot sequences in bat CoVs. We find that they all share some key qualitative features with the pseudoknot from SARS-CoV-2, notably the presence of conformers with two distinct fold topologies differing in whether or not the 5′ end of the RNA is threaded through a junction, and similar conformations for stem 1. However, they differed in the number of helices present, with half sharing the 3-helix architecture of the SARS-CoV-2 pseudoknot but two containing 4 helices and two others only 2. These structure models should be helpful for future work studying bat-CoV pseudoknots as potential therapeutic targets. Public Library of Science 2023-05-19 /pmc/articles/PMC10234561/ /pubmed/37205708 http://dx.doi.org/10.1371/journal.pcbi.1011124 Text en © 2023 Sekar et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sekar, Rohith Vedhthaanth
Oliva, Patricia J.
Woodside, Michael T.
Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title_full Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title_fullStr Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title_full_unstemmed Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title_short Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
title_sort modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234561/
https://www.ncbi.nlm.nih.gov/pubmed/37205708
http://dx.doi.org/10.1371/journal.pcbi.1011124
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