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

Academic Article
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Overview

authors

  • Childs-Disney, J. L.
  • Yildirim, I.
  • Park, HaJeung
  • Lohman, J. R.
  • Guan, L.
  • Tran, T.
  • Sarkar, P.
  • Schatz, G. C.
  • Disney, Matthew

publication date

  • February 2014

journal

  • ACS Chemical Biology  Journal

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.

subject areas

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Mice
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Myotonic Disorders
  • Myotonic Dystrophy
  • Nucleic Acid Conformation
  • RNA
  • Repetitive Sequences, Nucleic Acid
  • Small Molecule Libraries
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Identity

PubMed Central ID

  • PMC3944380

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb4007387

PubMed ID

  • 24341895
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Additional Document Info

start page

  • 538

end page

  • 550

volume

  • 9

issue

  • 2

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