Abstract
G-quadruplexes attract more and more attention in recent years. Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug development. As a motif existed in physiological condition, flanking sequences are an important part of G-quadruplexes but the study on the impact of flanking sequences on (G-quadruplex)-ligand binding is rarely reported. In this paper, the effects of flanking sequences on binding affinity between a series of unimolecular parallel-stranded G-quadruplex sequences derived from c-myc oncogene promoter (termed as c-myc G-quadruplexes) and their ligands are discussed in detail. The results showed that the flanking sequences on c-myc G-quadruplexes play key roles in (G-quadruplex)-ligand interaction. When a c-myc G-quadruplex is bound to its ligands, the flanking sequences might form a binding cavity above the terminal G-quartet, which could provide a suitable site for ligands to dock in. Moreover, the bases on flanking sequences could interact with ligand through π-π stacking, and finally form a sandwich-stacking mode (terminal G-quartet, ligand and bases on the flanking sequence). This mode could stabilize the (G-quadruplex)-ligand complex effectively and enhance the binding affinity dramatically. However, flanking sequences are also found to exhibit steric hindrance effect which could impede the (G-quadruplex)-ligand binding.
Highlights
G-quadruplex, flanking sequences, interaction mechanism, c-myc, cyanine dye Citation: Gai W, Yang Q F, Xiang J F, et al Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands
The cyanine dye MTC was synthesized according to Hamer [48] and Fichen’s [49] methods, and the purity was proved by mass spectrometry and nuclear magnetic resonance (NMR)
We will firstly focus on the sequence c-myc-core, which is part of the original sequence of NHE III1 and consists of 16 residues that are indispensable to form a integrate G-quadruplex structure
Summary
G-quadruplex, flanking sequences, interaction mechanism, c-myc, cyanine dye Citation: Gai W, Yang Q F, Xiang J F, et al Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands. Owing to the unique secondary motif, G-quadruplex is impervious to be attacked by enzymes targeting normal single-stranded or duplex DNA, and is able to regulate the transcription and replication of specific gene. A 22 bp variant of the NHE III1, 5′-[T4GA-(G7G8G9TG11G12G13GAG16G17G18TG20G21G22)-G AA25]-3′ (termed c-myc-2345), was designed which could form stable parallel-stranded chair form G-quadruplex structure in K+ solution [39,40]. NMRbased folding topology of c-myc-2345 in K+ solution had been resolved, which presents a typical unimolecular parallel-stranded G-quadruplex motif, including three G-tetrads, one two-residual loop (G14A15), two one-residual loops (T10 and T19) and two three-residual flanking sequences (T4G5A6 at 5′-end and G23A24A25 at 3′-end). Thanks to the stable Gquadruplex motif and the typical loop folding, c-myc-2345 is always considered as a model sequence in those in vitro (G-quadruplex)-ligands interaction studies [40]
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