5n5c: Difference between revisions
New page: '''Unreleased structure''' The entry 5n5c is ON HOLD until Paper Publication Authors: Garcia-Lopez, A., Wacker, A., Tessaro, F., Jonker, H.R.A., Richter, C., Comte, A., Berntenis, N., S... |
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==NMR solution structure of the TSL2 RNA hairpin== | |||
<StructureSection load='5n5c' size='340' side='right'caption='[[5n5c]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5n5c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N5C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5N5C FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5n5c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n5c OCA], [https://pdbe.org/5n5c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5n5c RCSB], [https://www.ebi.ac.uk/pdbsum/5n5c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5n5c ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes.,Garcia-Lopez A, Tessaro F, Jonker HRA, 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 Nat Commun. 2018 May 23;9(1):2032. doi: 10.1038/s41467-018-04110-1. PMID:29795225<ref>PMID:29795225</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5n5c" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Artero R]] | ||
[[Category: | [[Category: Berntenis N]] | ||
[[Category: | [[Category: Comte A]] | ||
[[Category: Joseph | [[Category: Ebeling M]] | ||
[[Category: | [[Category: Faustino I]] | ||
[[Category: | [[Category: Fournet G]] | ||
[[Category: | [[Category: Garcia-Lopez A]] | ||
[[Category: | [[Category: Goekjian P]] | ||
[[Category: | [[Category: Hatje K]] | ||
[[Category: | [[Category: Jonker HRA]] | ||
[[Category: | [[Category: Joseph B]] | ||
[[Category: | [[Category: Konieczny P]] | ||
[[Category: | [[Category: Metzger F]] | ||
[[Category: | [[Category: Orozco M]] | ||
[[Category: Richter C]] | |||
[[Category: Scapozza L]] | |||
[[Category: Schmucki R]] | |||
[[Category: Schwalbe H]] | |||
[[Category: Sciarra D]] | |||
[[Category: Tessaro F]] | |||
[[Category: Wacker A]] | |||
Latest revision as of 09:03, 19 June 2024
NMR solution structure of the TSL2 RNA hairpinNMR solution structure of the TSL2 RNA hairpin
Structural highlights
Publication Abstract from PubMedModification 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. Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes.,Garcia-Lopez A, Tessaro F, Jonker HRA, 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 Nat Commun. 2018 May 23;9(1):2032. doi: 10.1038/s41467-018-04110-1. PMID:29795225[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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