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Open AccessArticle

Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Lenin Hills 1, bldg. 40, 119991 Moscow, Russia
Lomonosov Moscow State University, Biology Faculty, Lenin Hills 1, bldg. 12, 119992 Moscow, Russia
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev avenue 8, 630090 Novosibirsk, Russia
Novosibirsk State University, Pirogov str. 2, 630090 Novosibirsk, Russia
Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Lenin Hills 1, bldg. 73, 119991 Moscow, Russia
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997 Moscow, Russia
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;
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.

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.

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.

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