DSSR-PyMOL cartoon-block schematics: PDB entry 6hmo

PDB-id

6hmo; DSSR-derived features in text and JSON formats

Class

RNA

Method

NMR

Summary

Solution structure of the RNA duplex formed by the 5'-end of u1snrna and the 5'-splice site of smn2 exon7 in complex with the smn-c5 splicing modifier

Reference

Campagne S, Boigner S, Rudisser S, Moursy A, Gillioz L, Knorlein A, Hall J, Ratni H, Clery A, Allain FH (2019): "Structural basis of a small molecule targeting RNA for a specific splicing correction." Nat.Chem.Biol., 15, 1191-1198. doi: 10.1038/s41589-019-0384-5.

Abstract

Splicing modifiers promoting SMN2 exon 7 inclusion have the potential to treat spinal muscular atrophy, the leading genetic cause of infantile death. These small molecules are SMN2 exon 7 selective and act during the early stages of spliceosome assembly. Here, we show at atomic resolution how the drug selectively promotes the recognition of the weak 5' splice site of SMN2 exon 7 by U1 snRNP. The solution structure of the RNA duplex formed following 5' splice site recognition in the presence of the splicing modifier revealed that the drug specifically stabilizes a bulged adenine at this exon-intron junction and converts the weak 5' splice site of SMN2 exon 7 into a stronger one. The small molecule acts as a specific splicing enhancer cooperatively with the splicing regulatory network. Our investigations uncovered a novel concept for gene-specific alternative splicing correction that we coined 5' splice site bulge repair.