title: Single-molecule study of the CUG repeat-MBNL1 interaction and its inhibition by small molecules.
abstract: Effective drug discovery and optimization can be accelerated by techniques capable of deconvoluting the complexities often present in targeted biological systems. We report a single-molecule approach to study the binding of an alternative splicing regulator, muscleblind-like 1 protein (MBNL1), to (CUG)n = 4,6 and the effect of small molecules on this interaction. Expanded CUG repeats (CUG(exp)) are the causative agent of myotonic dystrophy type 1 by sequestering MBNL1. MBNL1 is able to bind to the (CUG)n-inhibitor complex, indicating that the inhibition is not a straightforward competitive process. A simple ligand, highly selective for CUG(exp), was used to design a new dimeric ligand that binds to (CUG)n almost 50-fold more tightly and is more effective in destabilizing MBNL1-(CUG)4. The single-molecule method and the analysis framework might be extended to the study of other biomolecular interactions.
authors: Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
authors: Amin
authors: A
authors: Haghighat Jahromi
authors: Masayoshi
authors: M
authors: Honda
authors: Steven C
authors: SC
authors: Zimmerman
authors: Maria
authors: M
authors: Spies
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008856:Microscopy, Fluorescence / Q000379:methods; D012313:RNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries; D018911:Trinucleotide Repeats
chemical_list: D008024:Ligands; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D012313:RNA
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