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

• 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
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201703989

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.