Single-molecule study of the CUG repeat–MBNL1 interaction and its inhibition by small molecules

Amin Haghighat Jahromi; Masayoshi Honda; Steven C Zimmerman; Maria Spies

doi:10.1093/nar/gkt330

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Single-molecule study of the CUG repeat–MBNL1 interaction and its inhibition by small molecules

Journal article

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Single-molecule study of the CUG repeat–MBNL1 interaction and its inhibition by small molecules

Amin Haghighat Jahromi, Masayoshi Honda, Steven C Zimmerman and Maria Spies

Nucleic acids research, Vol.41(13), pp.6687-6697

07/2013

DOI: 10.1093/nar/gkt330

PMCID: PMC3711446

PMID: 23661680

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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.

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Title: Subtitle: Single-molecule study of the CUG repeat–MBNL1 interaction and its inhibition by small molecules
Creators: Amin Haghighat Jahromi - Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
Masayoshi Honda - Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
Steven C Zimmerman - Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
Maria Spies - Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.41(13), pp.6687-6697
Publisher: Oxford University Press
DOI: 10.1093/nar/gkt330
PMID: 23661680
PMCID: PMC3711446
ISSN: 0305-1048
eISSN: 1362-4962
Language: English
Date published: 07/2013
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984024414802771

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