{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:13:01Z","timestamp":1768515181341,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,23]]},"group-title":"Biophysics","reference-count":97,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T00:00:00Z","timestamp":1724371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  RNA repeat expansions fold into stable structures and cause microsatellite diseases such as Huntington\u2019s disease (HD), myotonic dystrophy type 1 (DM1), and spinocerebellar ataxias (SCAs). The trinucleotide expansion of r(CAG), or r(CAG)\n                  <jats:sup>exp<\/jats:sup>\n                  , causes both HD and SCA3, and the RNA\u2019s toxicity has been traced to its translation into polyglutamine (polyQ; HD) as well as aberrant pre-mRNA alternative splicing (SCA3 and HD). Previously, a small molecule,\n                  <jats:bold>1<\/jats:bold>\n                  , was discovered that binds to r(CAG)\n                  <jats:sup>exp<\/jats:sup>\n                  and rescues aberrant pre-mRNA splicing in patient-derived fibroblasts by freeing proteins bound to the repeats. Here, we report the structures of single r(CAG) repeat motif (5\u2019C\n                  <jats:underline>A<\/jats:underline>\n                  G\/3\u2019G\n                  <jats:underline>A<\/jats:underline>\n                  C where the underlined adenosines form a 1\u00d71 nucleotide internal loop) in complex with\n                  <jats:bold>1<\/jats:bold>\n                  and two other small molecules via nuclear magnetic resonance (NMR) spectroscopy combined with simulated annealing. Compound\n                  <jats:bold>2<\/jats:bold>\n                  was designed based on the structure of\n                  <jats:bold>1<\/jats:bold>\n                  bound to the RNA while\n                  <jats:bold>3<\/jats:bold>\n                  was selected as a diverse chemical scaffold. The three complexes, although adopting different 3D binding pockets upon ligand binding, are stabilized by a combination of stacking interactions with the internal loop\u2019s closing GC base pairs, hydrogen bonds, and van der Waals interactions. Molecular dynamics (MD) simulations performed with NMR-derived restraints show that the RNA is stretched and bent upon ligand binding with significant changes in propeller-twist and opening. Compound\n                  <jats:bold>3<\/jats:bold>\n                  has a distinct mode of binding by insertion into the helix, displacing one of the loop nucleotides into the major groove and affording a rod-like shape binding pocket. In contrast,\n                  <jats:bold>1<\/jats:bold>\n                  and\n                  <jats:bold>2<\/jats:bold>\n                  are groove binders. A series of single molecule magnetic force spectroscopy studies provide a mechanistic explanation for how bioactive compounds might rescue disease-associated cellular phenotypes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"608150v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.20.608150","type":"posted-content","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T10:07:26Z","timestamp":1724407646000},"source":"Crossref","is-referenced-by-count":0,"title":["NMR structures and magnetic force spectroscopy studies of small molecules binding to models of an RNA CAG repeat expansion"],"prefix":"10.64898","author":[{"given":"Amirhossein","family":"Taghavi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan L.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishshanthi","family":"Sinnadurai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Salthouse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Ozon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeline","family":"Feri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Fountain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Childs-Disney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8486-1796","authenticated-orcid":false,"given":"Matthew D.","family":"Disney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024082610001315000_2024.08.20.608150v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl046"},{"key":"2024082610001315000_2024.08.20.608150v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv222"},{"key":"2024082610001315000_2024.08.20.608150v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-3-8"},{"key":"2024082610001315000_2024.08.20.608150v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms10031226"},{"key":"2024082610001315000_2024.08.20.608150v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050001"},{"key":"2024082610001315000_2024.08.20.608150v1.6","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41569-024-01001-5","article-title":"Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease","volume":"21","year":"2024","journal-title":"Nat. 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