8R63

Solution structure of branaplam bound to the RNA duplex formed upon 5'-splice site recognition

8R63 の概要

• エントリーDOI: 10.2210/pdb8r63/pdb
• NMR情報: BMRB: 34879
• 分子名称: RNA (5'-R(*AP*UP*AP*CP*(PSU)P*(PSU)P*AP*CP*CP*UP*G)-3'), RNA (5'-R(P*GP*GP*AP*GP*UP*AP*AP*GP*UP*CP*U)-3'), Branaplam (3 entities in total)
• 機能のキーワード: rna splicing correction, small molecule splicing modifier, molecular glue, splicing
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 7368.72

構造登録者

Malard, F.,Campagne, S. (登録日: 2023-11-20, 公開日: 2024-03-06, 最終更新日: 2024-11-20)

主引用文献

Malard, F.,Wolter, A.C.,Marquevielle, J.,Morvan, E.,Ecoutin, A.,Rudisser, S.H.,Allain, F.H.T.,Campagne, S.
The diversity of splicing modifiers acting on A-1 bulged 5'-splice sites reveals rules for rational drug design.
Nucleic Acids Res., 52:4124-4136, 2024

PubMed Abstract: Pharmacological modulation of RNA splicing by small molecules is an emerging facet of drug discovery. In this context, the SMN2 splicing modifier SMN-C5 was used as a prototype to understand the mode of action of small molecule splicing modifiers and propose the concept of 5'-splice site bulge repair. In this study, we combined in vitro binding assays and structure determination by NMR spectroscopy to identify the binding modes of four other small molecule splicing modifiers that switch the splicing of either the SMN2 or the HTT gene. Here, we determined the solution structures of risdiplam, branaplam, SMN-CX and SMN-CY bound to the intermolecular RNA helix epitope containing an unpaired adenine within the G-2A-1G+1U+2 motif of the 5'-splice site. Despite notable differences in their scaffolds, risdiplam, SMN-CX, SMN-CY and branaplam contact the RNA epitope similarly to SMN-C5, suggesting that the 5'-splice site bulge repair mechanism can be generalised. These findings not only deepen our understanding of the chemical diversity of splicing modifiers that target A-1 bulged 5'-splice sites, but also identify common pharmacophores required for modulating 5'-splice site selection with small molecules.

PubMed: 38554107
DOI: 10.1093/nar/gkae201

実験手法

SOLUTION NMR