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 journalArticle

35 Citations (Scopus)

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

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Myotonic Dystrophy
Toxicity
Hydrogen
Hydrogen bonds
RNA
Molecular Dynamics Simulation
Molecules
Molecular dynamics
Nucleotides
Water
Computer simulation
Scaffolds
Structural analysis
Free energy
Crystal structure
Defects

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Childs-Disney, J. L., Yildirim, I., Park, H., Lohman, J. R., Guan, L., Tran, T., ... Disney, M. D. (2014). Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chemical Biology, 9(2), 538-550. https://doi.org/10.1021/cb4007387

Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. / Childs-Disney, Jessica L.; Yildirim, Ilyas; Park, Hajeung; Lohman, Jeremy R.; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C.; Disney, Matthew D.

In: ACS Chemical Biology, Vol. 9, No. 2, 21.02.2014, p. 538-550.

Research output: Contribution to journalArticle

Childs-Disney, JL, Yildirim, I, Park, H, Lohman, JR, Guan, L, Tran, T, Sarkar, P, Schatz, GC & Disney, MD 2014, 'Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity', ACS Chemical Biology, vol. 9, no. 2, pp. 538-550. https://doi.org/10.1021/cb4007387
Childs-Disney JL, Yildirim I, Park H, Lohman JR, Guan L, Tran T et al. Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chemical Biology. 2014 Feb 21;9(2):538-550. https://doi.org/10.1021/cb4007387
Childs-Disney, Jessica L. ; Yildirim, Ilyas ; Park, Hajeung ; Lohman, Jeremy R. ; Guan, Lirui ; Tran, Tuan ; Sarkar, Partha ; Schatz, George C. ; Disney, Matthew D. / Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 2. pp. 538-550.
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