Structural dynamics of single SARS-CoV-2 pseudoknot molecules reveal topologically distinct conformers.
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.
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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