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Structural dynamics of single SARS-CoV-2 pseudoknot molecules reveal topologically distinct conformers.
Neupane, Krishna; Zhao, Meng; Lyons, Aaron; Munshi, Sneha; Ileperuma, Sandaru M; Ritchie, Dustin B; Hoffer, Noel Q; Narayan, Abhishek; Woodside, Michael T.
  • Neupane K; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Zhao M; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Lyons A; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Munshi S; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Ileperuma SM; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Ritchie DB; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Hoffer NQ; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Narayan A; Department of Physics, University of Alberta, Edmonton, AB, Canada.
  • Woodside MT; Department of Physics, University of Alberta, Edmonton, AB, Canada. michael.woodside@ualberta.ca.
Nat Commun ; 12(1): 4749, 2021 08 06.
Article in English | MEDLINE | ID: covidwho-1345559
ABSTRACT
The RNA pseudoknot that stimulates programmed ribosomal frameshifting in SARS-CoV-2 is a possible drug target. To understand how it responds to mechanical tension applied by ribosomes, thought to play a key role during frameshifting, we probe its structural dynamics using optical tweezers. We find that it forms multiple structures two pseudoknotted conformers with different stability and barriers, and alternative stem-loop structures. The pseudoknotted conformers have distinct topologies, one threading the 5' end through a 3-helix junction to create a knot-like fold, the other with unthreaded 5' end, consistent with structures observed via cryo-EM and simulations. Refolding of the pseudoknotted conformers starts with stem 1, followed by stem 3 and lastly stem 2; Mg2+ ions are not required, but increase pseudoknot mechanical rigidity and favor formation of the knot-like conformer. These results resolve the SARS-CoV-2 frameshift signal folding mechanism and highlight its conformational heterogeneity, with important implications for structure-based drug-discovery efforts.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ribosomes / RNA, Viral / Frameshifting, Ribosomal / SARS-CoV-2 / Nucleic Acid Conformation Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-25085-6

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ribosomes / RNA, Viral / Frameshifting, Ribosomal / SARS-CoV-2 / Nucleic Acid Conformation Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-25085-6