6HMI

Solution structure of the RNA duplex formed by the 5'-end of U1snRNA and the 5'-splice site of SMN2 exon7

Summary for 6HMI

• Entry DOI: 10.2210/pdb6hmi/pdb
• NMR Information: BMRB: 34311
• Descriptor: RNA (5'-R(*AP*UP*AP*CP*(PSU)P*(PSU)P*AP*CP*CP*UP*G)-3'), RNA (5'-R(*GP*GP*AP*GP*UP*AP*AP*GP*UP*CP*U)-3') (2 entities in total)
• Functional Keywords: weak 5'-splice site, u1 snrna, spinal muscular atrophy, bulge nucleotide, rna
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 6975.24

Authors

Campagne, S.,Allain, F.H. (deposition date: 2018-09-12, release date: 2019-08-14, Last modification date: 2024-06-19)

Primary citation

Campagne, S.,Boigner, S.,Rudisser, S.,Moursy, A.,Gillioz, L.,Knorlein, A.,Hall, J.,Ratni, H.,Clery, A.,Allain, F.H.
Structural basis of a small molecule targeting RNA for a specific splicing correction.
Nat.Chem.Biol., 15:1191-1198, 2019

PubMed 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.

PubMed: 31636429
DOI: 10.1038/s41589-019-0384-5

Experimental method

SOLUTION NMR