2-Amino-1,8-naphthyridine Dimer (ANP77), a High-Affinity Binder to the Internal Loops of C/CC and T/CC Sites in Double-Stranded DNA
2-Amino-1,8-naphthyridine Dimer (ANP77), a High-Affinity Binder to the Internal Loops of C/CC and T/CC Sites in Double-Stranded DNA
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2-氨基-1,8-萘啶二聚体 (ANP77)，双链 DNA 中 C/CC 和 T/CC 位点内部环的高亲和力结合剂
DOI：
10.1021/acs.joc.1c02383
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Nakatani Kazuhiko
中科院分区：
文献类型：
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作者：
Das Bimolendu;Nagano Konami;Kawai Gota;Murata Asako;Nakatani Kazuhiko
靶向DNA结构起伏区域的小分子是一类重要的分子，作为化学探针用于研究这些结构在生物系统中的作用和神经系统疾病的发展。我们所描述的ANP77分子，其中一个三原子连接体连接两个2-氨基-1，8-萘啶在C7位，被发现在低pH值下与萘啶质子化形成堆积结构，并与双链DNA中由C/CC和T/CC组成的内环结合，亲和力分别为4.8和34.4 nm。质谱分析和等温滴定量热分析确定了ANP77结合的化学计量比为1：1，高锰酸盐化学足迹和核磁共振结构分析表明，T/CC中的T被迫向ANP77结合的螺旋外位置翻转。质子化堆积ANP77通过氢键与相邻的两个胞嘧啶相互作用，并通过反转CC相反的C或T而占据双链的位置。最后，本研究证实了ANP77与PIG3启动子的TG(T/C)CC重复序列和端粒重复序列CCCTAA结合的可能性。
Small molecules targeting DNA regions with structural fluctuation are an important class of molecule as chemical probes for studying the role of these structures in biological systems and the development of neurological disorders. The moleculeANP77we described here, where a three-atom linker connects two 2-amino-1,8-naphthyridines at the C7 position, was found to form stacked structure with protonation of naphthyridine at low pH, and bound to the internal loop consisting of C/CC and T/CC in double-stranded DNA with affinities of 4.8 and 34.4 nM, respectively. Mass spectrometry and isothermal titration calorimetry analyses determined the stoichiometry for the binding as 1:1, and chemical footprinting with permanganate and NMR structural analysis revealed that the T in the T/CC was forced to flip out toward an extrahelical position uponANP77binding. Protonated stackedANP77interacted with two adjacent cytosines through hydrogen bonding and occupied the position in the duplex by flipping out the C or T opposite CC. Finally, this study demonstrated the potential ofANP77for binding to the sequences of biological significance with the TG(T/C)CC repeat of thePIG3promoter and the telomere repeat CCCTAA.