0428同步年報-2021-全

Life Science 045 and the analogous RNA-DNA hybrid duplex r(GUGGGCCGAC)/d(GTCGGCCCAC) with the central -GGGCCG- region (G4C2 repeat motif) containing a core G4C2 repeat sequence ( Figs. 2(a) and 2(b) ). Detailed analysis of these complex nucleic-acid structures revealed many important features such as the broadening of the grooves and the sharp bend of the DNA duplex ( Fig. 2(c) ). In addition, the interactions at the interface of the crystal packing showed that the central region of the DNA duplexes is more flexible for direct or water-mediated intermolecular interactions ( Fig. 2(d) ). These specific natures of the DNA duplexes containing G4C2 repeats thus have the potential to serve as "hotspots" for the incorporation of external ligands. These unprecedented properties of the G4C2 DNA duplexes prompted the team to investigate various GC-selective DNA-binding compounds. Interestingly, biophysical characterization of several small-molecule compounds with G4C2 DNA revealed that metal-anthracene-based chromomycin complexes, (Ni II -(Chro) 2 ) and Co II -(Chro) 2 ), have the potential to stabilize firmly the DNA duplex ( Fig. 3(a) ). Chromomycin (Chro) is an aureolic acid-type metalloligand isolated from Streptomyces griseus that binds to DNA in the presence of divalent metal ions. Chro belongs to the class of groove-binding compounds and its affinity for GpC sites is influenced by the flanking base-pair sequence. To understand the molecular mechanism behind the preference of metal-Chro complexes for G4C2 repeat DNA, the team solved the complex structure of (Ni II -(Chro) 2 ) and a DNA duplex with G4C2 motif ( Fig. 3(b) ). Detailed structural analysis of the X-ray crystal structures identified that the metal-Chro complexes have extended specificity and bind the flanked G:C base pairs of the GGCC core. This binding of the ligand across the minor groove side also resulted in contraction of the groove and straightening of the DNA backbone ( Fig. 3(c) ). These specific structural changes in DNA resulting from Chro binding could therefore inhibit the formation of toxic transcripts in the resulting abnormal G4C2 expansion sequence and thus exert a therapeutic effect. Fig. 2 : (a-c) Overall structural features of the G4C2 motif-containing DNA and RNA-DNA hybrid duplexes compared with a typical A-form duplex. (d) The detailed crystal packing shows packing of type ‘base-pair into minor groove’ in G4C2DNA and RNA-DNA hybrid duplexes. [Reproduced from Ref. 4]