Molecular Recognition of 6′-<i>N</i>-5-Hexynoate Kanamycin A and RNA 1x1 Internal Loops Containing CA Mismatches

Tran, Tuan Anh; Disney, Matthew D.

doi:10.1021/bi101724h

Cited by 14 publications

(20 citation statements)

References 59 publications

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“…For example, A/C mismatches are isosteric with G•U wobble pairs, although their stability is influenced by nearest-neighbor identity (41). In pri-mir-16-1, the A/C mismatch is neither reactive to the SHAPE reagent or RNase A cleavage (Table 1); nor is it predicted to be highly disordered by MC-Fold, which is consistent with the structure of an A/C mismatch from the large ribosomal subunit found in an identical sequence context (42).…”

Section: Resultsmentioning

confidence: 99%

Ensemble Analysis of Primary MicroRNA Structure Reveals an Extensive Capacity To Deform near the Drosha Cleavage Site

et al. 2013

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Most non-coding RNAs function properly only when folded into complex 3D structures, but the experimental determination of these structures remains challenging. Understanding of primary miRNA maturation is currently limited by a lack of solved structures for non-processed forms of the RNA. SHAPE chemistry efficiently determines RNA secondary structural information with single-nucleotide resolution, providing constraints suitable for input into the MC-Pipeline software for refinement of 3D structure models. Here we combine these approaches to analyze three structurally diverse primary miRNAs, revealing deviations from canonical dsRNA structure in the stem adjacent to the Drosha cut site for all three. The necessity of these deformable sites for efficient processing is demonstrated through Drosha processing assays. The structure models generated herein support the hypothesis that deformable sequences spaced roughly once per turn of A-form helix, created by non-canonical structure elements, combine with the necessary single-stranded RNA:double-stranded RNA junction to define the correct Drosha cleavage site.

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Section: Resultsmentioning

confidence: 99%

Ensemble Analysis of Primary MicroRNA Structure Reveals an Extensive Capacity To Deform near the Drosha Cleavage Site

et al. 2013

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“…Dissociation constants were determined using an in-solution, fluorescence-based assay 20,21,48–51,54,55,58 . A selected RNA or RNA mixture was folded as described above.…”

Section: Methodsmentioning

confidence: 99%

Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations

Tran

Disney

2012

Nat Commun

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RNA is an important therapeutic target but information about RNA-ligand interactions is limited. Here we report a screening method that probes over 3,000,000 combinations of RNA motif-small molecule interactions to identify the privileged RNA structures and chemical spaces that interact. Specifically, a small molecule library biased for binding RNA was probed for binding to over 70,000 unique RNA motifs in a high throughput solution-based screen. The RNA motifs that specifically bind each small molecule were identified by microarray-based selection. In this library-versus-library or multidimensional combinatorial screening approach, hairpin loops (amongst a variety of RNA motifs) were the preferred RNA motif space that binds small molecules. Furthermore, it was shown that indole, 2-phenyl indole, 2-phenyl benzimidazole, and pyridinium chemotypes allow for specific recognition of RNA motifs. Since targeting RNA with small molecules is an extremely challenging area, these studies provide new information on RNA-ligand interactions that has many potential uses.

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“…X-ray crystallographic and NMR structure studies of ribosomes and rRNA fragments revealed that various aminoglycoside antibiotics inhibit translation by direct binding to architectural elements within the 16S rRNA and demonstrated that RNA can be specifically targeted by small molecules. The array of RNA motifs that can be specifically bound by small molecules and the chemotypes of those small molecules has been expanded through small molecule library-RNA motif library screens 1,41 . However, with few exceptions 30 , rational design of chemical inhibitors targeting specific RNA motifs has been less productive due in part to lack of reliable in silico and experimental tools for structure-based drug design.…”

Section: Resultsmentioning

confidence: 99%

2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

Nikonowicz

Zhang

Chang

et al. 2020

Preprint

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RNA helices are often punctuated with non-Watson-Crick features that can be the target of chemical compounds, but progress towards identifying small molecules specific for non-canonical elements has been slow. We have used a tandem UU:GA mismatch motif (5'-UG-3':5'-AU-3') embedded within the helix of an RNA hairpin as a model to identify compounds that bind the motif specifically. The three-dimensional structure of the RNA hairpin and its interaction with a small molecule compound identified through a virtual screen are presented. The G-A of the mismatch forms a sheared pair upon which the U-U base pair stacks. The hydrogen bond configuration of the U-U pair involves the O2 of the U adjacent to the G and the O4 of the U adjacent to the A. The G-A and U-U pairs are flanked by A-U and G-C base pairs, respectively, and the mismatch exhibits greater stability than when the motif is within the context of other flanking base pairs or when the 5'-3' orientation of the G-A and U-U is swapped.Residual dipolar coupling constants were used to generate an ensemble of structures against which a virtual screen of 64,480 small molecules was performed to identify candidate compounds that the motif specifically binds. The tandem mismatch was found to be specific for one compound, 2-amino-1,3-benzothiazole-6-carboxamide, which binds with moderate affinity but extends the motif to include the flanking A-U and G-C base pairs. The finding that affinity for the UU:GA mismatch is flanking sequence dependent emphasizes the importance of motif context and potentially increases the number of small non-canonical features within RNA that can be specifically targeted by small molecules.

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Molecular Recognition of 6′-N-5-Hexynoate Kanamycin A and RNA 1x1 Internal Loops Containing CA Mismatches

Cited by 14 publications

References 59 publications

Ensemble Analysis of Primary MicroRNA Structure Reveals an Extensive Capacity To Deform near the Drosha Cleavage Site

Ensemble Analysis of Primary MicroRNA Structure Reveals an Extensive Capacity To Deform near the Drosha Cleavage Site

Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations

2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

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