c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry
| Authors | |
|---|---|
| Year of publication | 2021 |
| Type | Article in Periodical |
| Magazine / Source | Nucleic Acids Research |
| MU Faculty or unit | |
| Citation | |
| Web | DOI: 10.1093/nar/gkab659 |
| Doi | http://dx.doi.org/10.1093/nar/gkab659 |
| Keywords | G-quadruplex; deoxyuridine nucleotide; pyrene; covalent probe; NMR spectroscopy; molecular dynamics |
| Attached files | |
| Description | Several sequences forming G-quadruplex are highly conserved in regulatory regions of genomes of different organisms and affect various biological processes like gene expression. Diverse G-quadruplex properties can be modulated via their interactionwith small polyaromatic molecules such as pyrene. To investigate how pyrene interacts with G-rich DNAs, we incorporated deoxyuridine nucleotide(s) with a covalently attached pyrene moiety (Upy)into a model system that forms parallel G-quadruplex structures. We individually substituted terminal positions and positions in the pentaloop of the c-kit2 sequence originating from the KIT proto-oncogene with Upy and performed a detailed NMR structural study accompanied with molecular dynamic simulations. Our results showed that incorporation into the pentaloop leads to structural polymorphism and in some cases also thermal destabilization. In contrast, terminal positions were found to cause a substantial thermodynamic stabilization while preserving topology of the parent c-kit2 G-quadruplex. Thermodynamic stabilization results from pi–pi stacking between the polyaromatic core of the pyrene moiety and guanine nucleotides of outer G-quartets. Thanks to the prevalent overall conformation, our structures mimic the G-quadruplex found in human KIT proto-oncogene and could potentially have antiproliferative effects on cancer cells. |
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