Tseng, W-H; Chang, C-K; Wu, P-C; Hu, N-J; Lee, G-H; Tzeng, C-C; Neidle, S; Tseng, W-H; Chang, C-K; Wu, P-C; Hu, N-J; Lee, G-H; Tzeng, C-C; Neidle, S; Hou, M-H; - view fewer (2017) Induced-Fit Recognition of CCG Trinucleotide Repeats by a Nickel-Chromomycin Complex Resulting in Large-Scale DNA Deformation. Angewandte Chemie International Edition , 56 (30) pp. 8761-8765. 10.1002/anie.201703989.

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Abstract

Small‐molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. Ni^{II}(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 Ni^{II} chelate itself. The DNA deformation of CCG repeats upon binding forms a GGCC tetranucleotide tract, which is recognized by Ni^{II}(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.

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