Journal
NATURE CHEMISTRY
Volume 3, Issue 10, Pages 782-787Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.1126
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Funding
- Camille and Henry Dreyfus Foundation
- Ohio Board of Regents
- NSF [CHE-1026532]
- NIH [R15 DK081191-01]
- BBSRC (UK)
- Cancer Research UK
- Core Research for Evolutional Science and Technology (CREST) of JST
- MEXT (Japan)
- BBSRC [BB/G008337/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G008337/1] Funding Source: researchfish
- Cancer Research UK [11961] Funding Source: researchfish
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1026532] Funding Source: National Science Foundation
- Grants-in-Aid for Scientific Research [09J00815] Funding Source: KAKEN
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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 K(d) of 490 +/- 80 nM. The free-energy change of binding obtained from a Hess-like process provides an identical K(d) for pyridostatin and a K(d) of 42 +/- 3 mu M 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.
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