title: Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity.
abstract: Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)(exp)) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5'CCUG/3'GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 Å. Structural analysis of the three 5'CCUG/3'GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na(+) and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5'CCUG/3'GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs-Disney
authors.affiliation: Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113.
authors.forename: Ilyas
authors.initials: I
authors.lastname: Yildirim
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.|Translational Research Institute, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Lohman
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: Lirui
authors.initials: L
authors.lastname: Guan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: Tuan
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0539.
authors.forename: Partha
authors.initials: P
authors.lastname: Sarkar
authors.affiliation: Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113.
authors.forename: George C
authors.initials: GC
authors.lastname: Schatz
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020967:Myotonic Disorders / Q000235:genetics*; D009223:Myotonic Dystrophy / Q000235:genetics; D009690:Nucleic Acid Conformation; D012313:RNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D012313:RNA