Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 30, Pages 11404-11422Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c03003
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Funding
- National Science Foundation RAPID Award from the Division of Mathematical Science [2030377]
- National Institutes of Health from the National Institute of General Medical Sciences
- Philip-Morris International
- National Institutes of Health [R35 GM140844, R01 GM101237, R01 HL111527]
- National Science Foundation RAPID Award from the Division of Chemistry [2030377]
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [2030377] Funding Source: National Science Foundation
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The FSE of SARS-CoV-2 is a promising target for Covid-19 therapy, but its structures and mechanisms pose challenges. Research suggests that the FSE may adopt multiple conformations, including the 3-stem H-type and HL-type pseudoknots, as well as the unknotted 3-way junction RNA. These findings advance our understanding of the virus frameshifting process and lifecycle, indicating potential avenues for therapeutic intervention.
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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