Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity

Jessica L. Childs-Disney, Ilyas Yildirim, Hajeung Park, Jeremy R. Lohman, Lirui Guan, Tuan Tran, Partha Sarkar, George C. Schatz, Matthew D. Disney

    Research output: Contribution to journalArticlepeer-review

    51 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)538-550
    Number of pages13
    JournalACS Chemical Biology
    Volume9
    Issue number2
    DOIs
    StatePublished - Feb 21 2014

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine

    Fingerprint

    Dive into the research topics of 'Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity'. Together they form a unique fingerprint.

    Cite this