Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation

Small‐molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. NiII(Chro)2 (Chro=chromomycin A3) binds specifically to the minor groove of (CCG)n repeats in duplex DNA, with unique fluorescence featu...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2017-07, Vol.56 (30), p.8761-8765
Main Authors: Tseng, Wen‐Hsuan, Chang, Chung‐ke, Wu, Pei‐Ching, Hu, Nien‐Jen, Lee, Gene‐Hsiang, Tzeng, Ching‐Cherng, Neidle, Stephen, Hou, Ming‐Hon
Format: Article
Language:English
Subjects:
Chemical bonds
Chemical compounds
Crystallography
Cytosine
Deformation
Deoxyribonucleic acid
Diagnostic agents
Diagnostic systems
Disease detection
Distortion
DNA
DNA deformation
DNA structure
Extrusion
Fluorescence
Guanine
Hydrogen
Hydrogen bonding
Hydrogen bonds
induced-fit recognition
neurological disease
Neurological diseases
Nickel
Nucleotides
Pharmacology
Recognition
Trinucleotide repeat diseases
Trinucleotide repeats
X-ray crystallography
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Summary:Small‐molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. NiII(Chro)2 (Chro=chromomycin A3) binds specifically to the minor groove of (CCG)n repeats in duplex DNA, with unique fluorescence features that may serve as a probe for disease detection. Crystallographic studies revealed that the specificity originates from the large‐scale spatial rearrangement of the DNA structure, including extrusion of consecutive bases and backbone distortions, with a sharp bending of the duplex accompanied by conformational changes in the NiII chelate itself. The DNA deformation of CCG repeats upon binding forms a GGCC tetranucleotide tract, which is recognized by NiII(Chro)2. The extruded cytosine and last guanine nucleotides form water‐mediated hydrogen bonds, which aid in ligand recognition. The recognition can be accounted for by the classic induced‐fit paradigm. NiII(Chro)2 (Chro=chromomycin A3) binds specifically to the minor groove of (CCG)n repeats in duplex DNA, with unique fluorescence features that may serve as a probe for disease detection. Crystallographic studies reveal that the specificity originates from the large‐scale spatial rearrangement of the DNA structure, with a sharp bending of the duplex accompanied by conformational changes in the NiII chelate itself.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201703989