A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands
| Autor: | Deepak Koirala, Raphaël Rodriguez, Yuta Sannohe, Hiroshi Sugiyama, Soma Dhakal, Shankar Balasubramanian, Beth Ashbridge, Hanbin Mao |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Chemistry
Stereochemistry Ligand General Chemical Engineering Kinetics DNA General Chemistry Telomere Ligands G-quadruplex Small molecule Article G-Quadruplexes Folding (chemistry) Dissociation constant Optical tweezers Aminoquinolines Biophysics Humans Thermodynamics Molecule Picolinic Acids Oxazoles Telomerase |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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