Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 30, Pages 8761-8765Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201703989
Keywords
DNA deformation; induced-fit recognition; neurological disease; trinucleotide repeats; X-ray crystallography
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Funding
- Ministry of Science and Technology, Taiwan [106-2912-I-005-501, 103-2113-M-005-007-MY3]
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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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