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- Title
Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine.
- Authors
Nilov, Dmitry; Maluchenko, Natalya; Kurgina, Tatyana; Pushkarev, Sergey; Lys, Alexandra; Kutuzov, Mikhail; Gerasimova, Nadezhda; Feofanov, Alexey; Švedas, Vytas; Lavrik, Olga; Studitsky, Vasily M.
- Abstract
7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD+ and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1–nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions.
- Subjects
POLY ADP ribose; FLUORESCENCE resonance energy transfer; DNA ligases; FLUORESCENCE anisotropy; MOLECULAR dynamics; DNA damage
- Publication
International Journal of Molecular Sciences, 2020, Vol 21, Issue 6, p2159
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms21062159