Molecular mechanisms of PARP-1 inhibitor 7-methylguanine

Dmitry Nilov, Natalya Maluchenko, Tatyana Kurgina, Sergey Pushkarev, Alexandra Lys, Mikhail Kutuzov, Nadezhda Gerasimova, Alexey Feofanov, Vytas Švedas, Olga Lavrik, Vasily M. Studitsky

Результат исследования: Научные публикации в периодических изданияхстатья

3 Цитирования (Scopus)

Аннотация

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.

Язык оригиналаанглийский
Номер статьи2159
Число страниц11
ЖурналInternational Journal of Molecular Sciences
Том21
Номер выпуска6
DOI
СостояниеОпубликовано - мар 2020

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  • Цитировать

    Nilov, D., Maluchenko, N., Kurgina, T., Pushkarev, S., Lys, A., Kutuzov, M., Gerasimova, N., Feofanov, A., Švedas, V., Lavrik, O., & Studitsky, V. M. (2020). Molecular mechanisms of PARP-1 inhibitor 7-methylguanine. International Journal of Molecular Sciences, 21(6), [2159]. https://doi.org/10.3390/ijms21062159