Journal
NUCLEIC ACIDS RESEARCH
Volume 41, Issue 13, Pages 6687-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt330
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Funding
- National Institutes of Health (NIH) [R01AR058361]
- Howard Hughes Medical Institute
- University of Iowa
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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.
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