Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres.

Guanhui Wu,Luying Chen,Danzhou Yang,Wenting Liu

doi:10.3390/molecules24081578

Abstract

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

Highlights

Human telomeres are essential DNA-nucleoprotein complexes capping the terminus of chromosomes to protect the chromosomes from end-to-end fusion and degradation [1,2]
Human telomeric DNA consists of TTAGGG tandem repeats 5–20 kb in length, terminating in a 30–500 nucleotide single-stranded 30 overhang [6]
Pt-tripod binds to the intramolecular hybrid-1 human telomeric G-quadruplex formed by the Tel26 sequence and forms well-defined monomeric and dimeric Pt-tripod-Tel26 complexes dependent on the drug-DNA ratio [63]

Summary

Introduction

Human telomeres are essential DNA-nucleoprotein complexes capping the terminus of chromosomes to protect the chromosomes from end-to-end fusion and degradation [1,2]. In the EPI-hybrid-2 complex, the second TTA loop adopts a conformation above the 50 -tetrad, which provides ideal orientation for the pairing interaction with lateral loop conformation above the 5′-tetrad, which provides ideal orientation for the pairing the 50 -flanking segment to form the highly stable capping structures of the T:T:A triad and T:T pair interaction with the 5′-flanking segment to form the highly stable capping structures of the T:T:A (Figure 5a,b). In the basket-type telomeric G-quadruplex structure, the diagonal loop and the 3′-flanking segments are both at the same end of the 5′-flanking (Figure 5d), sterically hindering the EPI binding. The EPI-hybrid-2 complex structure reveals several features which enable specific recognition the hybrid-2 human telomeric G-quadruplex. Pt-tripod binds to the intramolecular hybrid-1 human telomeric G-quadruplex formed by the Tel sequence and forms well-defined monomeric and dimeric Pt-tripod-Tel complexes dependent on the drug-DNA ratio [63].

Solution

Insights Obtained from the Complex Structures