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Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation
Author(s) -
Tseng WenHsuan,
Chang Chungke,
Wu PeiChing,
Hu NienJen,
Lee GeneHsiang,
Tzeng ChingCherng,
Neidle Stephen,
Hou MingHon
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201703989
Subject(s) - dna , cytosine , duplex (building) , guanine , biophysics , chemistry , chromomycin a3 , hydrogen bond , trinucleotide repeat expansion , stereochemistry , crystallography , genetics , biochemistry , biology , molecule , nucleotide , allele , heterochromatin , chromatin , gene , organic chemistry
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.