ArticleNucleic acids research2021
Recognition of single-stranded nucleic acids by small-molecule splicing modulators.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Kinetics, thermodynamics, and mechanisms of PMO interactions from computational molecular modeling.Molecular therapy. Nucleic acids · 2026Article
- Specificity and exon target space of splicing modifying compounds.Nature communications · 2026Article
- Depleting prion protein using splice-switching small molecules.bioRxiv : the preprint server for biology · 2026Article
- Systematic identification of variant-specific RNA structure-small molecule interactions exemplified by RNA G-quadruplexes.Nature communications · 2026Article
- Mechanistic studies of small molecule ligands selective to RNA single G bulges.Nucleic acids research · 2025Article
- Article
- Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region.Nature communications · 2025Article
- Specificity, synergy, and mechanisms of splice-modifying drugs.Nature communications · 2024Article
- Mechanism of Ligand Binding to Theophylline RNA Aptamer.Journal of chemical information and modeling · 2024Article
- Article
- Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region.bioRxiv : the preprint server for biology · 2023Article
- Global impact of aberrant splicing on human gene expression levels.bioRxiv : the preprint server for biology · 2023Article
- Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy.Nucleic acids research · 2023Article
- Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts.Protein science : a publication of the Protein Society · 2023Article
- Interaction between a fluoroquinolone derivative KG022 and RNAs: Effect of base pairs 3' adjacent to the bulged residues.Frontiers in molecular biosciences · 2023Article
- Gaussian Accelerated Molecular Dynamics in OpenMM.The journal of physical chemistry. B · 2022Article
- GLOW: A Workflow Integrating Gaussian-Accelerated Molecular Dynamics and Deep Learning for Free Energy Profiling.Journal of chemical theory and computation · 2022Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Risdiplam is the first approved small-molecule splicing modulator for the treatment of spinal muscular atrophy (SMA). Previous studies demonstrated that risdiplam analogues have two separate binding sites in exon 7 of the SMN2 pre-mRNA: (i) the 5'-splice site and (ii) an upstream purine (GA)-rich binding site. Importantly, the sequence of this GA-rich binding site significantly enhanced the potency of risdiplam analogues. In this report, we unambiguously determined that a known risdiplam analogue, SMN-C2, binds to single-stranded GA-rich RNA in a sequence-specific manner. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. We performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which captured spontaneous binding of a risdiplam analogue to the target nucleic acids. We uncovered, for the first time, a ligand-binding pocket formed by two sequential GAAG loop-like structures. The simulation findings were highly consistent with experimental data obtained from saturation transfer difference (STD) NMR and structure-affinity-relationship studies of the risdiplam analogues. Together, these studies illuminate us to understand the molecular basis of single-stranded purine-rich RNA recognition by small-molecule splicing modulators with an unprecedented binding mode.
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