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Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine.

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.

SUBMITTER: Nilov D

PROVIDER: S-EPMC7139824 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine.

Nilov Dmitry D Maluchenko Natalya N Kurgina Tatyana T Pushkarev Sergey S Lys Alexandra A Kutuzov Mikhail M Gerasimova Nadezhda N Feofanov Alexey A Švedas Vytas V Lavrik Olga O Studitsky Vasily M VM

International journal of molecular sciences 20200320 6

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<sup ...[more]

PMID: 32245127

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