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

Abstract

Small-molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. Ni (Chro) (Chro=chromomycin A3) binds specifically to the minor groove of (CCG) 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 chelate itself. The DNA deformation of CCG repeats upon binding forms a GGCC tetranucleotide tract, which is recognized by Ni (Chro) . 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.

Cooperative recognition of T:T mismatch by echinomycin causes structural distortions in DNA duplex

“…Their findings led them to propose the use of rhodium metalloinsertors as a basis for the development of new types of chemotherapeutic agents active against MMR-deficient cancers. We have also reported that many venerable antibiotic small-molecules may recognise mismatch sites within the non-canonical structures of repetitive DNA sequences ( 28 , 39 , 40 ). Since such sequences are hallmarks of many neurodegenerative diseases, we proposed that these antibiotic molecules could serve as a basis for the development of novel compounds that may either block DNA expansion or provide a read-out for disease detection ( 23 ).…”

A survey of recent unusual high-resolution DNA structures provoked by mismatches, repeats and ligand binding

“…Since TNR expansions are associated with the pathogenesis of various neurological diseases, the structural basis behind the ability to specifically recognize these mismatches is of considerable interest to both basic and applied researchers. Recently, recognition of nickel-chelated chromomycin dimer (Ni II (Chro) 2 ) to CCG TNRs has been shown to employ a classic induced-fit paradigm ( 103 ). Binding of the compound to the DNA induces large-scale deformations, including the extrusion, or flip-out, of two consecutive cytosines (Figure 9A ).…”

CoII(Chromomycin)2 Complex Induces a Conformational Change of CCG Repeats from i-Motif to Base-Extruded DNA Duplex

“…Previously, the Ni II (Chro) 2 complex has been shown to bind specifically to CCG TNRs via a “forced” induced-fit mechanism [ 15 ]. The Co II (Chro) 2 complex structure with DNA shows significant similarity in overall structure with that of the Ni II (Chro) 2 complex.…”

“…With this work, we complete our overview of chromomycin-based ligands containing a transition metal ion and their binding effects on repetitive DNA [ 15 , 33 , 45 , 46 ]. Our results provide additional clues to piece together the complete flow of how CCG DNA repeat amplification may arise, and provide a structural basis to speed the development and screening of specific drugs to treat diseases caused by the abnormal expansion of repeat DNA motifs.…”

“…Chro can bind to divalent metal ions and form a dimer, (Chro) 2 , that has a unique fluorescent emission under different environmental conditions [ 14 ]. Previously, Ni II (Chro) 2 has been shown to bind specifically to CCG TNRs via a “forced” induced-fit mechanism [ 15 ]. Upon binding to TNRs, Ni II (Chro) 2 exhibits a unique fluorescence signature which can potentially be used to identify fragile X syndrome in clinical specimens.…”