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High-affinity binding at quadruplex–duplex junctions: rather the rule than the exception
- Quadruplex-duplex (Q–D) junctions constitute unique structural motifs in genomic sequences. Through comprehensive calorimetric as well as high-resolution NMR structural studies, Q–D junctions with a hairpin-type snapback loop coaxially stacked onto an outer G-tetrad were identified to be most effective binding sites for various polycyclic quadruplex ligands. The Q–D interface is readily recognized by intercalation of the ligand aromatic core structure between G-tetrad and the neighboring base pair. Based on the thermodynamic and structural data, guidelines for the design of ligands with enhanced selectivity towards a Q–D interface emerge. Whereas intercalation at Q–D junctions mostly outcompete stacking at the quadruplex free outer tetrad or intercalation between duplex base pairs to varying degrees, ligand side chains considerably contribute to the selectivity for a Q–D target over other binding sites. In contrast to common perceptions, an appended side chain that additionally interacts within the duplex minor groove may confer only poor selectivity. Rather, the Q–D selectivity is suggested to benefit from an extension of the side chain towards the exposed part of the G-tetrad at the junction. The presented results will support the design of selective high-affinity binding ligands for targeting Q–D interfaces in medicinal but also technological applications.
Author: | Yoanes Maria Vianney, Klaus Weisz |
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URN: | urn:nbn:de:gbv:9-opus-104664 |
DOI: | https://doi.org/10.1093/nar/gkac1088 |
ISSN: | 1362-4962 |
Parent Title (English): | Nucleic Acids Research |
Publisher: | Oxford University Press |
Place of publication: | Oxford |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2022/11/23 |
Date of first Publication: | 2022/11/11 |
Release Date: | 2024/01/17 |
Volume: | 50 |
Issue: | 20 |
First Page: | 11948 |
Last Page: | 11964 |
Faculties: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie |
Collections: | Artikel aus DFG-gefördertem Publikationsfonds |
Licence (German): | Creative Commons - Namensnennung |