Photoswitchable molecular glue for RNA: reversible photocontrol of structure and function of the ribozyme

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Abstract
Single-stranded RNA folds into a variety of secondary and higher-order structures. Distributions and dynamics of multiple RNA conformations are responsible for the biological function of RNA. We here developed a photoswitchable molecular glue for RNA, which could reversibly control the association of two unpaired RNA regions in response to light stimuli. The photoswitchable molecular glue, NCTA, is an RNA-binding ligand possessing a photoisomerizable azobenzene moiety. Z-NCTA is an active ligand for the target RNA containing 5′-WGG-3′/5′-WGG-3′ (W = U or A) site and stabilizes its hybridized state, while its isomer E-NCTA is not. Photoreversible isomerization of NCTA enabled control of the secondary and tertiary structure of the target RNA. The RNA-cleaving activity of hammerhead ribozyme, where appropriate RNA folding is necessary, could be reversibly regulated by photoirradiation in cells treated with NCTA, demonstrating precise photocontrol of RNA structure and function by the photoswitchable molecular glue.
Funding Information
  • Grants in Aid for Scientific Research (18H02107, 22H02221)
  • Japan Society for the Promotion of Science
  • Japan Science and Technology Agency
  • CREST (JPMJCR20E6)

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