Graph, pseudoknot, and SARS-CoV-2 genomic RNA: A biophysical synthesis

Chen, Shijie

doi:10.1016/j.bpj.2021.01.030

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…In our prior work 22 (see also commentary 39 ), we defined target residues for drug binding and gene editing of the FSE from designed minimal mutants that dramatically transform the FSE conformation. Our RAG (RNA-As-Graphs) machinery represents RNA 2D structure as coarse-grained dual graphs, where double-stranded RNA helices are represented as vertices, and loop strands are edges.…”

Section: Introductionmentioning

confidence: 99%

“…However, depending on the modeling software and experimental technique, alternative secondary structures have been offered for SARS-CoV-2, both pseudoknotted and unknotted (see below). 20,23−25,28−34 In our prior work 22 (see also commentary 39 ), we defined target residues for drug binding and gene editing of the FSE from designed minimal mutants that dramatically transform the FSE conformation. Our RAG (RNA-As-Graphs) machinery represents RNA 2D structure as coarse-grained dual graphs, where double-stranded RNA helices are represented as vertices, and loop strands are edges.…”

Section: ■ Introductionmentioning

confidence: 99%

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To Knot or Not to Knot: Multiple Conformations of the SARS-CoV-2 Frameshifting RNA Element

et al. 2021

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The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic intervention against Covid-19. This small gene element employs a shifting mechanism to pause and backtrack the ribosome during translation between Open Reading Frames 1a and 1b, which code for viral polyproteins. Any interference with this process has a profound effect on viral replication and propagation. Pinpointing the structures adapted by the FSE and associated structural transformations involved in frameshifting has been a challenge. Using our graph-theory-based modeling tools for representing RNA secondary structures, “RAG” (RNA-As-Graphs), and chemical structure probing experiments, we show that the 3-stem H-type pseudoknot (3_6 dual graph), long assumed to be the dominant structure, has a viable alternative, an HL-type 3-stem pseudoknot (3_3) for longer constructs. In addition, an unknotted 3-way junction RNA (3_5) emerges as a minor conformation. These three conformations share Stems 1 and 3, while the different Stem 2 may be involved in a conformational switch and possibly associations with the ribosome during translation. For full-length genomes, a stem-loop motif (2_2) may compete with these forms. These structural and mechanistic insights advance our understanding of the SARS-CoV-2 frameshifting process and concomitant virus life cycle, and point to three avenues of therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

To Knot or Not to Knot: Multiple Conformations of the SARS-CoV-2 Frameshifting RNA Element

et al. 2021

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“…However, depending on the modeling software and experimental technique, alternative secondary structures have been offered for SARS-CoV-2, both pseudoknotted and unknotted (see below). 20,[23][24][25][28][29][30][31][32][33][34] In our prior work 22 (see also commentary 39 ), we defined target residues for drug binding and gene editing of the FSE from designed minimal mutants that dramatically transform the FSE conformation. Our RAG (RNA-As-Graphs) machinery represents RNA 2D structure as coarse-grained dual graphs, where doublestranded RNA helices are represented as vertices, and loop strands are edges.…”

Section: Introductionmentioning

confidence: 99%

“…In our prior work 20 (see also commentary 25 ), we defined target residues for drug binding and gene editing of the FSE from designed minimal mutants that dramatically transform the conformation of the FSE. Our RAG (RNA-As-Graphs) machinery represents RNA 2D structure as coarse-grained dual graphs, where doublestranded RNA helices are represented as vertices, and loop strands are edges.…”

Section: Introductionmentioning

confidence: 99%

To knot or not to knot: Multiple conformations of the SARS-CoV-2 frameshifting RNA element

Schlick

Zhu

Dey

et al. 2021

Preprint

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The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic intervention against Covid-19. This small gene element employs a shifting mechanism to pause and backtrack the ribosome during translation between Open Reading Frames 1a and 1b, which code for viral polyproteins. Any interference with this process has profound effect on viral replication and propagation. Pinpointing the structures adapted by the FSE and associated structural transformations involved in frameshifting has been a challenge. Using our graph-theory-based modeling tools for representing RNA secondary structures, "RAG" (RNA-As-Graphs), and chemical structure probing experiments, we show that the 3-stem H-type pseudoknot (3_6 dual graph), long assumed to be the dominant structure, is replaced by a different, HL-type 3-stem pseudoknot (3_3) as more residues, in particular the slippery site's 7 residues, are considered. In addition, an unknotted 3-way junction RNA (3_5) emerges as a minor conformation. These three conformations share Stems 1 and 3, while the different Stem 2 may be involved in a conformational switch and possibly associations with the ribosome during translation. These structural and mechanistic insights advance our understanding of the SARS-CoV-2 frameshifting process and concomitant virus life cycle, and point to three avenues of therapeutic intervention.

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“…Developing further and applying the RNA-As-Graphs (RAG) graph-theory tools for handling pseudoknots [90] , [91] , [92] , [93] , [94] to the SARS-CoV-2 FSE, the Schlick group has designed double mutants, shown in Fig. 5 B, that dramatically alter the FSE conformation (see [84] and accompanying New & Notable commentary [95] ). These mutations define target residues for drug binding and gene editing.…”

Section: Research Highlightsmentioning

confidence: 99%

Biomotors, viral assembly, and RNA nanobiotechnology: Current achievements and future directions

Rolband

Beasock

Wang

et al. 2022

Computational and Structural Biotechnology Journal

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Graph, pseudoknot, and SARS-CoV-2 genomic RNA: A biophysical synthesis

Cited by 6 publications

References 10 publications

To Knot or Not to Knot: Multiple Conformations of the SARS-CoV-2 Frameshifting RNA Element

To Knot or Not to Knot: Multiple Conformations of the SARS-CoV-2 Frameshifting RNA Element

To knot or not to knot: Multiple conformations of the SARS-CoV-2 frameshifting RNA element

Biomotors, viral assembly, and RNA nanobiotechnology: Current achievements and future directions

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