A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecu
Author: ["Deepak Koirala","Soma Dhakal","Beth Ashbridge","Yuta Sannohe","Raphaël Rodriguez","Hiroshi Sugiyama","Shankar Balasubramanian","Hanbin Mao"]
Publication: Nature Chemistry
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Abstract
Ligands that stabilize the formation of telomeric DNA G-quadruplexes have potential as cancer treatments, because the G-quadruplex structure cannot be extended by telomerase, an enzyme over-expressed in many cancer cells. Understanding the kinetic, thermodynamic and mechanical properties of small-molecule binding to these structures is therefore important, but classical ensemble assays are unable to measure these simultaneously. Here, we have used a laser tweezers method to investigate such interactions. With a force jump approach, we observe that pyridostatin promotes the folding of telomeric G-quadruplexes. The increased mechanical stability of pyridostatin-bound G-quadruplex permits the determination of a dissociation constant Kd of 490 ± 80 nM. The free-energy change of binding obtained from a Hess-like process provides an identical Kd for pyridostatin and a Kd of 42 ± 3 µM for a weaker ligand RR110. We anticipate that this single-molecule platform can provide detailed insights into the mechanical, kinetic and thermodynamic properties of liganded bio-macromolecules, which have biological relevance. G-quadruplex structures in telomeric DNA inhibit the action of telomerase — an enzyme over-expressed in many cancer cells. Small molecules that stabilize the formation of G-quadruplex structures are therefore of interest as potential cancer treatments. Here, a platform is described that allows the interactions between small-molecule ligands and human telomeric G-quadruplexes to be measured at the single-molecule level.
Cite this article
Koirala, D., Dhakal, S., Ashbridge, B. et al. A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands. Nature Chem 3, 782–787 (2011). https://doi.org/10.1038/nchem.1126