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Structural Insights into the Quadruplex-Duplex 3 ' Interface Formed from a Telomeric Repeat: A Potential Molecular Target

Krauss, IR; Ramaswamy, S; Neidle, S; Haider, S; Parkinson, GN; (2016) Structural Insights into the Quadruplex-Duplex 3 ' Interface Formed from a Telomeric Repeat: A Potential Molecular Target. Journal of the American Chemical Society , 138 (4) pp. 1226-1233. 10.1021/jacs.5b10492. Green open access

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Abstract

We report here on an X-ray crystallographic and molecular modeling investigation into the complex 3′ interface formed between putative parallel stranded G-quadruplexes and a duplex DNA sequence constructed from the human telomeric repeat sequence TTAGGG. Our crystallographic approach provides a detailed snapshot of a telomeric 3′ quadruplex–duplex junction: a junction that appears to have the potential to form a unique molecular target for small molecule binding and interference with telomere-related functions. This unique target is particularly relevant as current high-affinity compounds that bind putative G-quadruplex forming sequences only rarely have a high degree of selectivity for a particular quadruplex. Here DNA junctions were assembled using different putative quadruplex-forming scaffolds linked at the 3′ end to a telomeric duplex sequence and annealed to a complementary strand. We successfully generated a series of G-quadruplex–duplex containing crystals, both alone and in the presence of ligands. The structures demonstrate the formation of a parallel folded G-quadruplex and a B-form duplex DNA stacked coaxially. Most strikingly, structural data reveals the consistent formation of a TAT triad platform between the two motifs. This triad allows for a continuous stack of bases to link the quadruplex motif with the duplex region. For these crystal structures formed in the absence of ligands, the TAT triad interface occludes ligand binding at the 3′ quadruplex–duplex interface, in agreement with in silico docking predictions. However, with the rearrangement of a single nucleotide, a stable pocket can be produced, thus providing an opportunity for the binding of selective molecules at the interface.

Type: Article
Title: Structural Insights into the Quadruplex-Duplex 3 ' Interface Formed from a Telomeric Repeat: A Potential Molecular Target
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/jacs.5b10492
Publisher version: http://doi.org/10.1021/jacs.5b10492
Language: English
Additional information: Copyright © 2016 American Chemical Society. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, DNA QUADRUPLEX, CRYSTAL-STRUCTURES, LOOP FLEXIBILITY, HUMAN GENOME, C-MYC, RECOGNITION, LIGANDS, RNA, DRUG, INHIBITION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1483466
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