Molecular mechanisms of PARP-1 inhibitor 7-methylguanineстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
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Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 22 апреля 2020 г.
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.