Ligand-inducible formation of RNA pseudoknot

Matsumoto, Saki; Hong, Changfeng; Otabe, Takahiro; Murata, Akira; Nakatani, Kazuhiko

doi:10.1016/j.bmcl.2013.04.037

Cited by 11 publications

(11 citation statements)

References 32 publications

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“…[15] NCTn speciesa re naphthyridine tetramers, each consisting of two NCD molecules connected by af lexible aliphatic alkyl linker of n methylene units (n = 5, 6, 7, and 8). [24,25] NCTnsw ere not effective in the activation of HHR1, butc ould induce complex formation in two RNA hairpin loops, as well as pseudoknot formation in particularR NAs, depending on n. [24,25] NCTnsf unction as molecular glue for the specific RNAs. Conversely,( Z)-NCTS was not effective in inducing these RNA structures (unpublished data).…”

Section: Activation Of Hammerheadr Ibozyme Through Tertiary Structurementioning

confidence: 99%

Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules

Dohno

Nakatani

2019

ChemBioChem

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We introduce the concept of molecular glues for RNA, in which specific RNA‐binding small molecules induce designed structural changes in target functional RNAs, resulting in modulation of the functions. (Z)‐NCTS is an RNA‐mismatch‐binding small molecule that recognizes 5′‐r(XGG)‐3′/5′‐r(XGG)‐3′ sequences (X=U or A) and acts as a molecular glue for RNA. The binding of (Z)‐NCTS brings two distinct 5′‐r(XGG)‐3′ domains into contact with each other, and this can result in higher‐order structural changes of target RNAs. We applied (Z)‐NCTS to induce the formation of a proposed tertiary structure of a ribozyme together with activation of RNA‐cleaving ability. The concept of a molecular glue could inspire new small‐molecule‐based strategies for regulating biological functions: a synthetic small molecule targeting functional RNAs could regulate the RNA structure and function.

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Section: Activation Of Hammerheadr Ibozyme Through Tertiary Structurementioning

confidence: 99%

Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules

Dohno

Nakatani

2019

ChemBioChem

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“…In another study, the Nakatani laboratory demonstrated ligand-induced −1 ribosomal frameshifting via stabilization of a pseudoknot structure in mRNA upon ligand binding (Figure 3d). 67,68 These studies demonstrated that it is feasible to design ligands that modulate RNA function through the induction of a predefined change in RNA structure.…”

Section: Example Studiesmentioning

confidence: 99%

Understanding the Contributions of Conformational Changes, Thermodynamics, and Kinetics of RNA–Small Molecule Interactions

Juru

Hargrove

2019

ACS Chem. Biol.

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The implication of RNA in multiple cellular processes beyond protein coding has revitalized interest in the development of small molecules for therapeutically targeting RNA and for further probing its cellular biology. However, the process of rationally designing such small molecule probes is hampered by the paucity of information about fundamental molecular recognition principles of RNA. In this Review, we summarize two important and often underappreciated aspects of RNA-small molecule recognition: RNA conformational dynamics and the biophysical properties of interactions of small molecules with RNA, specifically thermodynamics and kinetics. While conformational flexibility is often said to impede RNA ligand development, the ability of small molecules to influence the RNA conformational landscape can have a significant effect on the cellular functions of RNA. An analysis of the conformational landscape of RNA and the interactions of individual conformations with ligands can thus guide the development of new small molecule probes, which needs to be investigated further. Additionally, while it is common practice to quantify the binding affinities (K a or K d) of small molecules for biomacromolecules as a measure of their activity, further biophysical characterization of their interaction can provide a deeper understanding. Studies that focus on the thermodynamic and kinetic parameters for interaction between RNA and ligands are next discussed. Finally, this Review provides the reader with a perspective on how such in-depth analysis of biophysical characteristics of the interaction of RNA and small molecules can impact our understanding of these interactions and how they will benefit the future design of small molecule probes.

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“…Among a series of naphthyridine derivatives that bind to DNA/RNA G–G mismatches, Z ‐NCTS is the most effective for the HHR1 activation (Supporting Information, Figure S5). The chemical structures of the linker that connects naphthyridines have a significant effect on the selectivity of targeting particular RNA structures.…”

Section: Figurementioning

confidence: 99%

Restoration of Ribozyme Tertiary Contact and Function by Using a Molecular Glue for RNA

2017

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Some RNAc lasses require folding into the proper higher-order structures to exert their functions.H ammerhead ribozyme (HHR) requires af olding conformation stabilized by tertiary interaction for full activity.Arationally engineered HHR was developed that was inactive,b ut could be activated by as ynthetic RNA-binding ligand, naphthyridine carbamate tetramer with Z-stilbene linker (Z-NCTS). Binding of Z-NCTS could induce the formation of an active folding structure and therebyr estore ribozyme activity,w here Z-NCTS acts as amolecular glue to bring two isolated RNAloops into contact with each other.N ext, we designed aZ -NCTS-responsive genetic switch using the HHR sequence inserted into the 3' untranslated region as ac is-acting element. We demonstrated that the rationally designed ribozyme switch enabled regulation of gene expression by Z-NCTS and was functional in mammalian cells.

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Ligand-inducible formation of RNA pseudoknot

Cited by 11 publications

References 32 publications

Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules

Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules

Understanding the Contributions of Conformational Changes, Thermodynamics, and Kinetics of RNA–Small Molecule Interactions

Restoration of Ribozyme Tertiary Contact and Function by Using a Molecular Glue for RNA

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