Institute of Genomics and Bioinformatics, National Chung Hsing University, 250 Kuo-kuang Rd., Taichung, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, Taiwan.
Angew Chem Int Ed Engl. 2017 Jul 17;56(30):8761-8765. doi: 10.1002/anie.201703989. Epub 2017 Jun 14.
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.
小分子化合物靶向 DNA 中的三核苷酸重复序列，具有作为许多神经疾病治疗或诊断剂的巨大潜力。Ni(Chro)(Chro=chromomycin A3)特异性结合到双链 DNA 中的(CCG)重复的小沟中，具有独特的荧光特征，可作为疾病检测的探针。晶体学研究表明，这种特异性源于 DNA 结构的大规模空间重排，包括连续碱基的挤出和骨架扭曲，双链伴随着镍配合物本身构象变化的急剧弯曲。CCG 重复序列结合后形成一个 GGCC 四核苷酸片段，被 Ni(Chro)识别。挤出的胞嘧啶和最后一个鸟嘌呤核苷酸形成水介导的氢键，有助于配体识别。这种识别可以用经典的诱导契合范式来解释。
