Conformational readout of RNA by small ligands

Kligun, Efrat; Mandel-Gutfreund, Yael

doi:10.4161/rna.24682

Cited by 16 publications

(20 citation statements)

References 44 publications

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“…Further we extracted the RNA interfaces and compared the structural features of the RNA to the features extracted from a data set of all RNA interfaces of the RNA-binding domains. Consistent with the knowledge that most RBPs bind ssRNA 33,42,43 we observed an overall preference for non-paired nucleotides in the RNA interfaces bound to the proteins, except for interfaces extracted from proteins belonging to the dsRBD family, which expectedly were enriched with the standard Watson-Crick pairing (WWcis). While for most RBPs we did not noticed any preference for a unique RNA-conformation at the RNA-protein interfaces, in some domain families, specifically in the RRM, we observed a significant enrichment for the rare RNA conformations, C2' endo and syn at the binding interface ( Table 1).…”

Section: Resultssupporting

confidence: 88%

“…32 Further, we demonstrated that nucleotides possessing the rare conformations are preferentially involved in direct interactions between RNA and small ligand. 33 Here we show that rare RNA conformations are also prevalent among nucleotides which bind proteins, specifically via the RRM domain. This suggests that RNA conformation may contribute to the recognition code by which proteins can specifically identify their targets.…”

Section: Introductionmentioning

confidence: 73%

“…The final set included 198 domains (Supplementary File S1). The "All RNA" was extracted from Kligun et al 33 Structural properties calculations Characterizing the structural properties of RNA within the interfaces was conducted by MC-annotate program. 38 The features were extracted as described in 39 using an in-house Perl script converting the MC-annotate output files into binary format, i.e., each nucleotide was given a score of "1" when a specific property was present and a score of "0" when it was absent.…”

Section: Data Extractionmentioning

confidence: 99%

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The role of RNA conformation in RNA-protein recognition

Kligun

Mandel-Gutfreund

2015

RNA Biology

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Interactions between protein and RNA play a key role in many biological processes in the gene expression pathway. Those interactions are mediated through a variety of RNA-binding protein domains, among them the highly abundant RNA recognition motif (RRM). Here we studied protein-RNA complexes from different RNA binding domain families solved by NMR and x-ray crystallography. Characterizing the structural properties of the RNA at the binding interfaces revealed an unexpected number of nucleotides with unusual RNA conformations, specifically found in RNA-RRM complexes. Moreover, we observed that the RNA nucleotides that are directly involved in interactions with the RRM domains, via hydrogen bonds and hydrophobic contacts, are significantly enriched with unique RNA conformations. Further examination of the sequences binding the RRM domain showed a preference for G nucleotides in syn conformation to precede or to follow U nucleotides in the anti-conformation, and U nucleotides in C2' endo conformation to precede U and G nucleotides possessing the more common C3' endo conformation. These findings imply a possible mode of RNA recognition by the RRM domains which enables the recognition of a wide variety of different RNA sequences and shapes. Overall, this study suggests an additional way by which the RRM domain recognizes its RNA target, involving a conformational readout.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 73%

Section: Data Extractionmentioning

confidence: 99%

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The role of RNA conformation in RNA-protein recognition

Kligun

Mandel-Gutfreund

2015

RNA Biology

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“…These interactions fine-tune the specificity of RNA interactions by determining structure at the 3D level [22]. Interestingly, non-canonical pairs were also found to be involved in ligand binding sites [8,19], which corroborates with further findings showing that some secondary structure motifs can specify ligand binding [6,48].…”

Section: Rna Structuresupporting

confidence: 75%

Augmented base pairing networks encode RNA-small molecule binding preferences

Oliver

Mallet

Gendron

et al. 2019

Preprint

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Recent studies have identified small RNA-binding molecules with potential for therapeutic applications including novel antibiotics, antivirals, protein synthesis controllers, and CRISPR activators. As RNA binding data accumulates, machine learning methods are becoming attractive approaches to accelerate the discovery of RNA-targeting drugs. While atomic level representations of molecular systems are regarded as a critical step for physics-based and data-driven drug design, the singularity and hierarchical organization of RNA structures challenges this paradigm. In this work, we present a machine learning framework for assisting in the discovery of small RNA-binding molecules from graphical representations of RNA structures. A key feature of our tool is that it does not rely on manual feature engineering or costly physical simulations. Instead, we extract molecule-binding information directly from known RNA-ligand complexes by combining graph embedding methods with machine learning models. Given only the graph representation of an RNA site as input, our tool is able to reliably predict chemical features, also known as fingerprints, of the observed ligands. The resulting fingerprints can be used to classify RNA sites according to their binding preferences, screen databases for promising ligands, or act as constraints for generating novel ligands. We show consistent performance for across ligand classes in enriching the known binder from a larger ligand library. As a validation, we applied this method to successfully identify binding residues in unbound RNA structures for three different riboswitches. These results also suggest that small molecule binding preferences in RNA can be extracted directly from the nucleotide pairing level.

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“…Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts.…”

mentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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Conformational readout of RNA by small ligands

Cited by 16 publications

References 44 publications

The role of RNA conformation in RNA-protein recognition

The role of RNA conformation in RNA-protein recognition

Augmented base pairing networks encode RNA-small molecule binding preferences

Unveiling the druggable RNA targets and small molecule therapeutics

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