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Open AccessArticle

Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

1
Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Lenin Hills 1, bldg. 40, 119991 Moscow, Russia
2
Lomonosov Moscow State University, Biology Faculty, Lenin Hills 1, bldg. 12, 119992 Moscow, Russia
3
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev avenue 8, 630090 Novosibirsk, Russia
4
Novosibirsk State University, Pirogov str. 2, 630090 Novosibirsk, Russia
5
Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Lenin Hills 1, bldg. 73, 119991 Moscow, Russia
6
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997 Moscow, Russia
7
Fox Chase Cancer Center, Cottman Avenue 333, Philadelphia, PA 19111-2497, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 2159; https://doi.org/10.3390/ijms21062159
Received: 28 January 2020 / Revised: 12 March 2020 / Accepted: 17 March 2020 / Published: 20 March 2020
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. View Full-Text
Keywords: 7-methylguanine; poly(ADP-ribose) polymerase 1; inhibitor; nucleosome; trapping; docking; molecular dynamics; fluorescence anisotropy; spFRET microscopy 7-methylguanine; poly(ADP-ribose) polymerase 1; inhibitor; nucleosome; trapping; docking; molecular dynamics; fluorescence anisotropy; spFRET microscopy
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MDPI and ACS Style

Nilov, D.; Maluchenko, N.; Kurgina, T.; Pushkarev, S.; Lys, A.; Kutuzov, M.; Gerasimova, N.; Feofanov, A.; Švedas, V.; Lavrik, O.; Studitsky, V.M. Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine. Int. J. Mol. Sci. 2020, 21, 2159. https://doi.org/10.3390/ijms21062159

AMA Style

Nilov D, Maluchenko N, Kurgina T, Pushkarev S, Lys A, Kutuzov M, Gerasimova N, Feofanov A, Švedas V, Lavrik O, Studitsky VM. Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine. International Journal of Molecular Sciences. 2020; 21(6):2159. https://doi.org/10.3390/ijms21062159

Chicago/Turabian Style

Nilov, Dmitry; Maluchenko, Natalya; Kurgina, Tatyana; Pushkarev, Sergey; Lys, Alexandra; Kutuzov, Mikhail; Gerasimova, Nadezhda; Feofanov, Alexey; Švedas, Vytas; Lavrik, Olga; Studitsky, Vasily M. 2020. "Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine" Int. J. Mol. Sci. 21, no. 6: 2159. https://doi.org/10.3390/ijms21062159

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