5OR0

NMR derived model of the 5'-splice site of SMN2 in complex with the 5'-end of U1 snRNA

Summary for 5OR0

• Entry DOI: 10.2210/pdb5or0/pdb
• NMR Information: BMRB: 34171
• Descriptor: RNA (5'-R(P*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') (2 entities in total)
• Functional Keywords: 5'-splice site, smn2, small muscular atrophy, rna
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 6975.24

Authors

Campagne, S.,Clery, A.,Allain, F.H. (deposition date: 2017-08-14, release date: 2017-08-30, Last modification date: 2024-06-19)

Primary citation

Sivaramakrishnan, M.,McCarthy, K.D.,Campagne, S.,Huber, S.,Meier, S.,Augustin, A.,Heckel, T.,Meistermann, H.,Hug, M.N.,Birrer, P.,Moursy, A.,Khawaja, S.,Schmucki, R.,Berntenis, N.,Giroud, N.,Golling, S.,Tzouros, M.,Banfai, B.,Duran-Pacheco, G.,Lamerz, J.,Hsiu Liu, Y.,Luebbers, T.,Ratni, H.,Ebeling, M.,Clery, A.,Paushkin, S.,Krainer, A.R.,Allain, F.H.,Metzger, F.
Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers.
Nat Commun, 8:1476-1476, 2017

PubMed Abstract: Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.

PubMed: 29133793
DOI: 10.1038/s41467-017-01559-4

Experimental method

SOLUTION NMR