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.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Haghighat Jahromi A,Honda M,Zimmerman SC,Spies Mdoi
10.1093/nar/gkt330subject
Has Abstractpub_date
2013-07-01 00:00:00pages
6687-97issue
13eissn
0305-1048issn
1362-4962pii
gkt330journal_volume
41pub_type
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