9CPD

Structures of small molecules bound to RNA repeat expansions that cause Huntington's disease-like 2 and myotonic dystrophy type 1

Summary for 9CPD

• Entry DOI: 10.2210/pdb9cpd/pdb
• NMR Information: BMRB: 31188
• Descriptor: RNA (5'-R(*GP*AP*CP*AP*GP*CP*UP*GP*CP*UP*GP*UP*C)-3'), 4-[(3-methoxyphenyl)amino]-2-methylquinoline-6-carboximidamide (2 entities in total)
• Functional Keywords: cug repeats, rna, myotonic dystrophy type 1, dm1, 5'cug/3'guc
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 8573.36

Authors

Chen, J.L.,Taghavi, A.,Disney, M.D.,Fountain, M.A.,Childs-Disney, J.L. (deposition date: 2024-07-18, release date: 2024-08-07, Last modification date: 2024-08-14)

Primary citation

Chen, J.L.,Taghavi, A.,Frank, A.J.,Fountain, M.A.,Choudhary, S.,Roy, S.,Childs-Disney, J.L.,Disney, M.D.
NMR structures of small molecules bound to a model of a CUG RNA repeat expansion.
Bioorg.Med.Chem.Lett., 111:129888-129888, 2024

PubMed Abstract: 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). The RNA folds into a hairpin structure with a periodic array of 1 × 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). 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.

PubMed: 39002937
DOI: 10.1016/j.bmcl.2024.129888

Experimental method

SOLUTION NMR