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Ligand Binding to Dynamically Populated G-Quadruplex DNA
M. Aznauryan, SL. Noer, CW. Pedersen, JL. Mergny, MP. Teulade-Fichou, V. Birkedal
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
DFF-0602-01670
Danish Council for Independent Research
DFF-6110-00623
Danish Council for Independent Research
G4invivo-661415
European Union's Horizon 2020 research and innovation programme
CZ.02.1.01/0.0/0.0/15_003/0000477
European Union's Horizon 2020 research and innovation programme
ERDF
PubMed
33450114
DOI
10.1002/cbic.202000792
Knihovny.cz E-zdroje
- MeSH
- chinoliny chemie metabolismus MeSH
- G-kvadruplexy * MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- ligandy * MeSH
- rezonanční přenos fluorescenční energie MeSH
- simulace molekulární dynamiky MeSH
- telomery chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Several small-molecule ligands specifically bind and stabilize G-quadruplex (G4) nucleic acid structures, which are considered to be promising therapeutic targets. G4s are polymorphic structures of varying stability, and their formation is dynamic. Here, we investigate the mechanisms of ligand binding to dynamically populated human telomere G4 DNA by using the bisquinolinium based ligand Phen-DC3 and a combination of single-molecule FRET microscopy, ensemble FRET and CD spectroscopies. Different cations are used to tune G4 polymorphism and folding dynamics. We find that ligand binding occurs to pre-folded G4 structures and that Phen-DC3 also induces G4 formation in unfolded single strands. Following ligand binding to dynamically populated G4s, the DNA undergoes pronounced conformational redistributions that do not involve direct ligand-induced G4 conformational interconversion. On the contrary, the redistribution is driven by ligand-induced G4 folding and trapping of dynamically populated short-lived conformation states. Thus, ligand-induced stabilization does not necessarily require the initial presence of stably folded G4s.
Department of Chemistry and iNANO center Aarhus University Gustav Wieds Vej 14 8000 Aarhus Denmark
Institute of Biophysics of the CAS 61265 Brno Czech Republic
Present address Univ Bordeaux INSERM CNRS ARNA U1212 UMR 5320 IECB 33600 Pessac France
Citace poskytuje Crossref.org
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- $a Several small-molecule ligands specifically bind and stabilize G-quadruplex (G4) nucleic acid structures, which are considered to be promising therapeutic targets. G4s are polymorphic structures of varying stability, and their formation is dynamic. Here, we investigate the mechanisms of ligand binding to dynamically populated human telomere G4 DNA by using the bisquinolinium based ligand Phen-DC3 and a combination of single-molecule FRET microscopy, ensemble FRET and CD spectroscopies. Different cations are used to tune G4 polymorphism and folding dynamics. We find that ligand binding occurs to pre-folded G4 structures and that Phen-DC3 also induces G4 formation in unfolded single strands. Following ligand binding to dynamically populated G4s, the DNA undergoes pronounced conformational redistributions that do not involve direct ligand-induced G4 conformational interconversion. On the contrary, the redistribution is driven by ligand-induced G4 folding and trapping of dynamically populated short-lived conformation states. Thus, ligand-induced stabilization does not necessarily require the initial presence of stably folded G4s.
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