TY - JOUR
T1 - Single-molecule study of the CUG repeat-MBNL1 interaction and its inhibition by small molecules
AU - Jahromi, Amin Haghighat
AU - Honda, Masayoshi
AU - Zimmerman, Steven C.
AU - Spies, Maria
N1 - Funding Information:
National Institutes of Health (NIH) [R01AR058361 to S.C.Z.]; Howard Hughes Medical Institute (Early Career Scientist Award to M.S.). Funding for open access charge: NIH and University of Iowa start-up funds.
PY - 2013/7
Y1 - 2013/7
N2 - 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 (CUGexp) 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 CUGexp, 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.
AB - 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 (CUGexp) 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 CUGexp, 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.
UR - http://www.scopus.com/inward/record.url?scp=84880523180&partnerID=8YFLogxK
U2 - 10.1093/nar/gkt330
DO - 10.1093/nar/gkt330
M3 - Article
C2 - 23661680
AN - SCOPUS:84880523180
SN - 0305-1048
VL - 41
SP - 6687
EP - 6697
JO - Nucleic acids research
JF - Nucleic acids research
IS - 13
ER -