5N5C

NMR solution structure of the TSL2 RNA hairpin

Summary for 5N5C

• Entry DOI: 10.2210/pdb5n5c/pdb
• NMR Information: BMRB: 34100
• Descriptor: RNA (19-MER) (1 entity in total)
• Functional Keywords: terminal stem-loop 2 survival motor neuron, rna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 6048.63

Authors

Garcia-Lopez, A.,Wacker, A.,Tessaro, F.,Jonker, H.R.A.,Richter, C.,Comte, A.,Berntenis, N.,Schmucki, R.,Hatje, K.,Sciarra, D.,Konieczny, P.,Fournet, G.,Faustino, I.,Orozco, M.,Artero, R.,Goekjian, P.,Metzger, F.,Ebeling, M.,Joseph, B.,Schwalbe, H.,Scapozza, L. (deposition date: 2017-02-13, release date: 2018-03-14, Last modification date: 2024-06-19)

Primary citation

Garcia-Lopez, A.,Tessaro, F.,Jonker, H.R.A.,Wacker, A.,Richter, C.,Comte, A.,Berntenis, N.,Schmucki, R.,Hatje, K.,Petermann, O.,Chiriano, G.,Perozzo, R.,Sciarra, D.,Konieczny, P.,Faustino, I.,Fournet, G.,Orozco, M.,Artero, R.,Metzger, F.,Ebeling, M.,Goekjian, P.,Joseph, B.,Schwalbe, H.,Scapozza, L.
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes.
Nat Commun, 9:2032-2032, 2018

PubMed Abstract: Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5' splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.

PubMed: 29795225
DOI: 10.1038/s41467-018-04110-1

Experimental method

SOLUTION NMR