View source for 9cpj


==Structures of small molecules bound to RNA repeat expansions that cause Huntington's disease-like 2 and myotonic dystrophy type 1==
<StructureSection load='9cpj' size='340' side='right'caption='[[9cpj]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9cpj]] is a 2 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=9CPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CPJ 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=9cpj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9cpj OCA], [https://pdbe.org/9cpj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9cpj RCSB], [https://www.ebi.ac.uk/pdbsum/9cpj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9cpj ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to these structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)(exp). The RNA folds into a hairpin structure with a periodic array of 1 x 1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBPs) and hence the source of its gain-of-function. Here, we report nuclear magnetic resonance (NMR)-refined structures of single 5'CUG/3'GUC motifs in complex with three different small molecules, a di-guandinobenzoate (1), a derivative of 1 where the guanidino groups have been exchanged for imidazole (2), and a quinoline with improved drug-like properties (3). These structures were determined using NMR spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1, 2, and 3 formed stacking and hydrogen bonding interactions with the 5'CUG/3'GUC motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)(exp). As the first ever reported structures of a r(CUG) repeat bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.

NMR structures of small molecules bound to a model of a CUG RNA repeat expansion.,Chen JL, Taghavi A, Frank AJ, Fountain MA, Choudhary S, Roy S, Childs-Disney JL, Disney MD Bioorg Med Chem Lett. 2024 Jul 14;111:129888. doi: 10.1016/j.bmcl.2024.129888. PMID:39002937<ref>PMID:39002937</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9cpj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen JL]]
[[Category: Childs-Disney JL]]
[[Category: Disney MD]]
[[Category: Fountain MA]]
[[Category: Taghavi A]]