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• W3186331361 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." @default.
• W3186331361 created "2021-08-02" @default.
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• W3186331361 date "2021-07-20" @default.
• W3186331361 modified "2023-10-14" @default.
• W3186331361 title "Recognition of single-stranded nucleic acids by small-molecule splicing modulators" @default.
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• W3186331361 doi "https://doi.org/10.1093/nar/gkab602" @default.
• W3186331361 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8373063" @default.
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