Cooperative Heteroligand Interaction with G-Quadruplexes Shows Evidence of Allosteric Binding.
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ABSTRACT: Although allosteric binding of small molecules is commonplace in protein structures, it is rather rare in DNA species such as G-quadruplexes. By using CD melting, here, we found binding of the small-molecule ligands PDS and L2H2-6OTD to the telomeric DNA G-quadruplex was cooperative. Mass spectrometry indicated a 1:1:1 ratio in the ternary binding complex of the telomeric G-quadruplex, PDS, and L2H2-6OTD. Compared to the binding of each individual ligand to the G-quadruplex, single-molecule mechanical unfolding assays revealed a significantly decreased dissociation constant when one ligand is evaluated in the presence of another. This demonstrates that cooperative binding of PDS and L2H2-6OTD to the G-quadruplex is allosteric, which is also supported by the mass spectra data that indicated the ejection of coordinated sodium ions upon binding of the heteroligands to the G-quadruplex. The unprecedented observation of the allosteric ligand binding to higher-ordered structures of DNA may help to design more effective ligands to target non-B DNA species involved in many critical cellular processes.
SUBMITTER: Pandey S
PROVIDER: S-EPMC7511437 | biostudies-literature |
REPOSITORIES: biostudies-literature
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